Clinical trial NCT03252431
Conditions: Breast Cancer Neutropenia
Sponsor: EVIVE Biotechnology
Start date: 2018-04-12; Completion date: 2020-03-05
Enrollment: 393 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, multi-center, single dose, open-label and Neulasta controlled phase 3 study to evaluate the efficacy and safety of F-627 in women with Stage I - III invasive breast cancer receiving chemotherapy treatment.

Detailed description:
This is a Phase III, global, two arm, open label clinical study will randomize approximately 400 female subjects (approximately 200 per arm) with Stage I - III invasive breast cancer who are to receive neoadjuvant or adjuvant myelotoxic TC chemotherapy treatment (docetaxel + cyclophosphamide, 75 and 600 mg/m2, respectively). Subjects in this study will be those who are scheduled to undergo at least four 21-day cycles of chemotherapy treatment. Subjects may be scheduled for more than 4 cycles of chemotherapy; however, study participation will be limited to a subject's first 4 cycles.

The primary objective of this study will be to evaluate the efficacy of F-627 given as a single fixed dose (20 mg) pre-filled syringe as compared to Neulasta® standard dosing (6 mg) in the first chemotherapy cycle. The primary endpoint will be the duration of grade 4 (severe) neutropenia - the number of days in which the patient has had an absolute neutrophil count (ANC \<0.5 x 10\^9/L) observed in chemotherapy cycle 1.

Approximately 24 hours after chemotherapy completion in each cycle (Day 2 of the cycle), subjects will receive one of the following treatments:

Arm 1: F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles.

Arm 2: 6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Randomization will occur in an equal ratio (1:1) using a central randomization system (IWRS) on Day 1 of the study, the day of chemotherapy administration for the first chemotherapy cycle.

This study is open-label, however, study drug injections are to be administered separately by qualified study personnel to allow study investigators to remain blinded and perform study assessments without knowledge of treatment assignment.

Arms: arm 1: F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. arm 2: 6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles
Interventions: intervention 1: F-627 intervention 2: Neulasta
Intervention descriptions: intervention 1: single dose pre-filled syringe intervention 2: single dose pre-filled syringe

Protocol documents:
Prot_000.pdf: 


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INTRODUCTORY AND CONFIDENTIALITY STATEMENT 
 
This protocol has been prepared according to the ICH E6(R1) Guidelines for Good Clinical 
Practice (GCP) and FDA GCP regulations: 21 CFR 312, 21 CFR 50, 21 CFR 56, and associated 
guidelines.  
 
This document contains confidential information of Generon (Shanghai) Corporation Ltd. that 
should not be disclosed to anyone other than the recipient study staff, members of the Ethics 
Committee, Institutional Review Board, Data and Safety Monitoring Committee, and Regulatory 
Authorities. This information cannot be used for any purpose other than the evaluation or conduct 
of the clinical study without the prior written consent of Generon (Shanghai) Corporation Ltd. 
 
PRINCIPAL INVESTIGATOR'S STATEMENT 
 
I, the undersigned, have reviewed this protocol, including Appendices, and I agree to conduct the 
clinical study as described (subject to any amendments). Any changes in procedure will only be 
made if necessary to protect the safety, rights or welfare of study subjects. 
 
I agree to conduct in person or to supervise the study. I agree to ensure that all who assist me in 
the conduct of the study are aware of their obligations. 
 
      Site Investigator:  
 
 
                                                  Site Number: 
 
 
 
 
 
 
 
Signature: ______________________  
Date: _______________________ 
 
 
 
 
 
 
 
 




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STUDY SYNOPSIS 
Protocol Number: 
GC-627-05 
Title: 
A Phase III, Randomized, Multi-Centre, Open-Label, Fixed Dose, 
Neulasta® Active-Controlled Clinical Trial of F-627 in Women with Breast 
Cancer Receiving Myelotoxic Chemotherapy 
Study Phase: 
Phase III 
Name of Product: 
F-627 
Name of Active 
Ingredient: 
Recombinant fusion protein with human granulocyte-colony stimulating factor 
(hG-CSF) fused to human immunoglobulin IgG2-Fc. 
Indication: 
F-627 is indicated to decrease the incidence of infection, as manifested by 
febrile neutropenia, in patients with non-myeloid malignancies receiving 
myelosuppressive anti-cancer therapy associated with a clinically significant 
incidence of febrile neutropenia. 
Sponsor: 
Generon (Shanghai) Corporation  
Building 9, 787 Kang Qiao Road, 
Shanghai, PRC 201315 
Tel: 8621-61760866 
Fax: 8621-61760865 
Name of Sponsor 
Contact: 
William L. Daley, MD, MPH, MBA 
Generon (Shanghai) Corporation 
Name of Principal 
Investigators: 
John Glaspy, MD 
UCLA 
Test Product, Dose, 
and Mode of 
Administration:  
F-627 is to be administered subcutaneously (SC) approximately 24 hours after 
chemotherapy administration in each 21-day cycle of chemotherapy treatment 
(up to 4 cycles). Dose: 20 mg single fixed dose pre-filled syringe for 
subcutaneous injection. 
Concurrent Control: 
6 mg/dose Neulasta®   
Objectives and Study 
Endpoints: 
Objective:  
The primary objective of this study is to evaluate the efficacy of F-627 given 
as a single fixed dose (20 mg) pre-filled syringe as compared to Neulasta® 
standard dosing (6 mg) in the first chemotherapy cycle. 
Primary Efficacy Endpoint: 
The primary endpoint is the duration of grade 4 (severe) neutropenia (ANC < 
0.5 x 109/L) defined as the number of days in which the subject has had an 
ANC < 0.5 × 109/L during cycle 1 of their chemotherapy treatment.  
Secondary Efficacy Endpoints: 
For all secondary and additional analyses, the F-627 group will be compared to 
the Neulasta® group.  
The secondary efficacy endpoints are as follows: 




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scheduled to undergo at least four 21-day cycles of chemotherapy treatment. 
Subjects may be scheduled for more than 4 cycles of chemotherapy; however, 
study participation will be limited to a subject’s first 4 cycles. 
The primary objective of this study will be to evaluate the efficacy of F-627 
given as a single fixed dose (20 mg) pre-filled syringe as compared to 
Neulasta® standard dosing (6 mg) in the first chemotherapy cycle. The 
primary endpoint will be the duration of grade 4 (severe) neutropenia (ANC 
<0.5 x 109/L) observed in chemotherapy cycle 1. A non-inferiority analysis 
will be used with a margin of 0.6 days will be used to compare the F-627 arm 
to the Neulasta® arm with respect to the duration of severe neutropenia. 
Approximately 24 hours after chemotherapy completion in each cycle (Day 2 
of the cycle), subjects will receive one of the following treatments: 
Arm 1: F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of 
each of 4 chemotherapy cycles. 
Arm 2: 6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 
chemotherapy cycles  
Randomization will occur in an equal ratio (1:1) using a central randomization 
system (IWRS) on Day 1 of the study, the day of chemotherapy administration 
for the first chemotherapy cycle.  
This study is open-label, however, study drug injections are to be administered 
separately by qualified study personnel to allow study investigators to remain 
blinded and perform study assessments without knowledge of treatment 
assignment.   
A central lab will conduct all ANC measurements used for analysis, however, 
in the event a subject’s central lab samples are missing or compromised in 
quality during the 1st chemotherapy cycle, local lab ANC values are to be used.  
Additonally,  local lab results may be used to monitor subject safety during the 
course of the study and are to be reported when associated with AEs. 
Subjects will remain in their randomized study arm for each of the subsequent 
3 chemotherapy cycles. Subjects will return for an End of Treatment (EOT) 
visit approximately 20 days after the final study drug administration and for a 
follow up visit approximately 6 months from the date of  the subject’s final 
study drug administration. 
Study Sites: 
This study will be conducted in up to 50 clinical centers in North & South 
America, Europe, and Asia. 
Subject Population: 
The study population is planned to consist of at least 400 female subjects ≥18 
years of age diagnosed with Stage I-III breast cancer. 
Eligibility: 
Subjects are eligible for study entry if they meet the following inclusion 
criteria: ≥18 years of age; diagnosis Stage I-III invasive breast cancer that 
requires neoadjuvant or adjuvant chemotherapy; Eastern Cooperative 
Oncology Group (ECOG) performance status ≤2; white blood cell (WBC) 
count ≥4.0 × 109/L; hemoglobin ≥11.5 g/dL; platelet count ≥150 × 109/L; 
adequate renal, hepatic and cardiac function; and scheduled for TC 
chemotherapy treatment. Subjects will be excluded from the study if their 
disease had progressed while receiving a taxane regimen, if they have 
undergone radiation therapy within 4 weeks of enrollment or chemotherapy 
within 180 days of screening, or if they have undergone a bone marrow or 
stem-cell transplantation. 


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Subjects with a history of prior malignancy other than breast cancer may enter 
the study if the malignancy is in remission. Subjects that have used or may 
have to use of G-CSF within 6 weeks of the screening period or a drug or 
substance that may potentiate the release of neutrophils are excluded (i.e., 
sargramostim or filgrastim). 
Duration of Treatment  The duration of study treatment will be a total of approximately 84 days with a 
screening phase, an EOT visit approximately 20 days after last study dose and 
a follow up visit 6 months after last study dose.  
Subjects will be dosed according to their treatment arm randomization 
occurring on Day 1 of their first chemotherapy cycle. Subjects will be dosed on 
Day 1 of each subsequent chemotherapy cycle for a total of up to 4, 21-day 
cycles. To begin full-dose chemotherapy on Day 1 of the next cycle (Day 22 of 
the previous cycle), it is recommended that patients have a base hemoglobin of 
at least 11.5 g/dl, ANC >2.0 x 109/L and a platelet count >100 x 109/L.   
Clinical assessments will occur for all subjects during the screening period 
(Day -15 to Day -1). Clinical assessments are cycle specific upon study entry: 
Chemotherapy Cycle 1:  Subjects are required to return to the clinic 24 hours 
after chemotherapy administration for study drug dosing.  
During the first chemotherapy cycle, post chemotherapy, study subjects are 
required to return to the study site for daily blood draws to track ANC 
behavior.  Subjects will return for cycle days 2-10, and each day thereafter, 
until the subject’s ANC levels reach ≥2.0 × 109/L, post-nadir, and then the 
subject is to return three days later for their final chemotherapy cycle ANC 
draw.   
Chemotherapy Cycles 2, 3, 4:   
Subjects are required to return to the clinic 24 hours after chemotherapy 
administration for study drug dosing. This will typically occur on study Days 
23, 44, and 65 for cycles 2, 3, and 4 respectively.  These days may differ 
slightly as the actual time frame will be dependent upon the subject’s 
individual chemotherapy schedule, as noted above. 
For cycles 2, 3, and 4, subjects are required to return to the study site every 
other day for blood draws to track ANC behavior post chemotherapy 
administration.  Subjects will return every other day from cycle day 3 to cycle 
day 11 and every other thereafter until the subject’s ANC levels reach 
≥2.0×109/L, post-nadir and then three days later.   
If the ANC level of a subject is <0.5 × 109/L for two consecutive visits, the 
subject must return the following day and then daily for an ANC blood draw 
until the ANC level is ≥2.0 × 109/L. 
Subject Assignment: 
Eligible subjects will be randomized to 1 of 2 study arms: 
Arm 1: F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of 
each of 4 chemotherapy cycles. 
Arm 2: 6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 
chemotherapy cycles. 
Sample Size:  
The assumptions used to calculate the study sample size are based on the 
results from the GC-627-02 Phase II study. For subjects dosed with TC 
chemotherapy, the difference in the duration of severe neutropenia for F-627 in 
this study as compared to Neulasta® was 0.3 and 0.1 days, for the 240 and 
320 µg/kg arms respectively, with an observed standard deviation of 0.28 days 




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TABLE OF CONTENTS 
STUDY SYNOPSIS ................................................................................................................................ 4 
1 
PROTOCOL IDENTIFIERS ......................................................................................................... 12 
2 
BACKGROUND INFORMATION ............................................................................................... 13 
2.1 
Name and Description of Investigational Product ............................................................... 13 
2.1.1 
Characteristics and Description ............................................................................. 13 
2.1.2 
Physical and Chemical Characteristics of the Drug Substance ............................. 13 
2.2 
Studies and Findings ............................................................................................................ 13 
2.2.1 
Non-Clinical Studies ............................................................................................. 13 
2.2.2 
Clinical Studies and Previous Human Usage ........................................................ 13 
2.3 
Description and Justification for Route of Administration, Dosage and Regimen, and 
Treatment Period ................................................................................................................. 16 
2.3.1 
Route of Administration ........................................................................................ 16 
2.3.2 
Justification for Clinical Dose ............................................................................... 16 
2.3.3 
Dosage Regimen ................................................................................................... 17 
2.4 
Study Conduct ..................................................................................................................... 17 
2.5 
Study Population .................................................................................................................. 17 
3 
TRIAL OBJECTIVES AND ENDPOINTS ................................................................................... 17 
3.1 
Primary Efficacy Objective ................................................................................................. 17 
3.2 
Primary Efficacy Endpoint .................................................................................................. 17 
3.3 
Secondary Efficacy Endpoints ............................................................................................. 18 
3.4 
Additional Endpoints ........................................................................................................... 18 
3.5 
Safety Objective .................................................................................................................. 18 
3.6 
.................................................................................................. 18 
4 
TRIAL DESIGN AND RATIONALE ........................................................................................... 19 
4.1 
Trial Design ......................................................................................................................... 19 
4.2 
Rationale .............................................................................................................................. 20 
4.3 
Schematic Diagram and Trial Design .................................................................................. 21 
5 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................................. 21 
5.1 
Subject Inclusion Criteria .................................................................................................... 21 
5.2 
Subject Exclusion Criteria ................................................................................................... 22 
5.3 
Subject Withdrawal from Study .......................................................................................... 22 
5.3.1 
Criteria for Subject Withdrawal ............................................................................ 22 
5.3.2 
Procedures for Subject Withdrawal ....................................................................... 23 
5.3.3 
Replacements for Withdrawn Subjects ................................................................. 23 
5.3.4 
Follow-Up of Withdrawn Subjects ........................................................................ 23 
5.3.5 
Documentation ...................................................................................................... 23 
6 
TRIAL PROCEDURES ................................................................................................................. 23 
6.1 
Measures to Avoid Bias ....................................................................................................... 23 
6.1.1 
Randomization ...................................................................................................... 23 
6.1.2 
Simultaneous Utilization of All Arms ................................................................... 24 


 
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6.2 
Trial Treatment and Dosage and Regimen of Investigational Products .............................. 24 
6.2.1 
Treatment Dose ..................................................................................................... 24 
6.2.2 
Description of the Dosage Form, Packaging and Labeling of the 
Investigational Product .......................................................................................... 24 
6.2.3 
Comparator Drug ................................................................................................... 24 
6.2.4 
Investigational Drug Dose Schedule ..................................................................... 25 
6.3 
Duration of Subject Participation ........................................................................................ 25 
6.4 
Hold and Stop Rules ............................................................................................................ 25 
6.4.1 
Stop Rules for Subjects (Study Drug Discontinuation) ......................................... 25 
6.4.2 
End of Treatment and Follow-up Visits ................................................................ 25 
6.5 
Accountability Procedures ................................................................................................... 25 
6.6 
Electronic Case Report Forms ............................................................................................. 26 
7 
TREATMENT OF SUBJECTS ..................................................................................................... 26 
7.1 
Dosing .................................................................................................................................. 26 
7.2 
Concomitant Medications .................................................................................................... 26 
7.3 
Approved Medications ......................................................................................................... 26 
7.4 
Medications Not Permitted .................................................................................................. 26 
7.5 
Compliance .......................................................................................................................... 27 
8 
ASSESSMENT OF EFFICACY .................................................................................................... 27 
8.1 
Efficacy Parameters ............................................................................................................. 27 
9 
ASSESSMENT OF SAFETY ........................................................................................................ 27 
9.1 
Safety Parameters ................................................................................................................ 27 
9.1.1 
Standard Safety Parameters ................................................................................... 27 
9.2 
The Methods and Timing for Assessing, Recording and Analyzing Safety Parameters ..... 27 
9.2.1 
Medical History and Clinical Signs and Symptoms .............................................. 27 
9.2.2 
Physical Examination ............................................................................................ 27 
9.2.3 
Reporting ............................................................................................................... 28 
9.3 
Procedures for Eliciting Reports of and Recording and Reporting Adverse Events and 
Intercurrent Illnesses ............................................................................................................ 28 
9.4 
Type and Duration of Follow-Up of Subjects after Adverse Events ................................... 28 
9.5 
Defining, Grading and Reporting Adverse Events .............................................................. 28 
9.5.1 
Adverse Events ...................................................................................................... 28 
9.5.2 
Definition .............................................................................................................. 28 
9.5.3 
Serious Adverse Events ......................................................................................... 29 
9.5.4 
Grading Adverse Events ........................................................................................ 29 
9.5.5 
Exposure in Utero .................................................................................................. 30 
9.5.6 
Relationship to Study Therapy .............................................................................. 31 
9.5.7 
Abnormal Laboratory Findings ............................................................................. 31 
9.5.8 
Eliciting Adverse Event Information .................................................................... 32 
9.5.9 
Reporting Requirements (Serious and Non-Serious) ............................................ 32 
10 STATISTICAL ANALYSIS .......................................................................................................... 33 
10.1 Study Endpoints ................................................................................................................... 33 
10.1.1 
Primary Efficacy Endpoint .................................................................................... 33 


 
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10.1.2 
Secondary Efficacy Endpoints .............................................................................. 33 
10.1.3 
Additional Endpoints ............................................................................................. 34 
10.1.4 
Safety Endpoints ................................................................................................... 34 
10.1.5 
 .................................................................................... 34 
10.2 Statistical Methods............................................................................................................... 34 
10.2.1 
Efficacy Analysis .................................................................................................. 34 
10.2.2 
Primary Efficacy Analysis ..................................................................................... 34 
10.2.3 
Secondary Efficacy Analysis ................................................................................. 35 
10.2.4 
Additional Endpoints ............................................................................................. 35 
10.2.5 
Safety Analysis ...................................................................................................... 35 
10.2.6 
 ..................................................................................... 35 
10.2.7 
Sample Size Calculation ........................................................................................ 35 
10.3 Criteria for Termination and Sponsor Discontinuation Criteria .......................................... 36 
10.4 Procedure for Accounting for Missing, Unused and Spurious Data .................................... 36 
10.5 Procedure for Reporting Deviations from the Original Statistical Plan and Justification ... 36 
10.6 Selection of Subjects Included in the Analysis .................................................................... 36 
10.6.1 
Safety Analyses Set ............................................................................................... 36 
10.6.2 
Intent to Treat Analysis Set ................................................................................... 36 
10.6.3 
Per Protocol Analysis Set ...................................................................................... 36 
10.7 Six(6)-month Long-term Follow-up Analysis ..................................................................... 37 
11 DIRECT ACCESS TO SOURCE DOCUMENTS ........................................................................ 37 
12 QUALITY CONTROL AND QUALITY ASSURANCE ............................................................. 37 
13 ETHICS .......................................................................................................................................... 37 
13.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ........................... 37 
13.2 Ethical Conduct of the Trial ................................................................................................ 38 
13.3 Patient Information and Consent ......................................................................................... 38 
14 DATA HANDLING AND RECORD KEEPING .......................................................................... 38 
14.1 Electronic Case Report Forms (eCRFs)............................................................................... 38 
14.2 Record Retention ................................................................................................................. 39 
15 FINANCING AND INSURANCE ................................................................................................ 39 
16 PUBLICATION POLICY .............................................................................................................. 39 
17 REFERENCES ............................................................................................................................... 40 
18 APPENDICES ............................................................................................................................... 42 
18.1 Trial Procedures and Activities ........................................................................................... 42 
18.2 Study Flow Chart ................................................................................................................. 45 
18.3 Central Lab Locations .......................................................................................................... 46 
18.4 Definition of Abbreviations and Definitions of Terms ........................................................ 47 
 


 
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1 PROTOCOL IDENTIFIERS 
 
 
Therapeutic area: 
Oncology 
Product: 
F-627 
Indication: 
Decrease the incidence of infection, as manifested by febrile 
neutropenia, in patients with non-myeloid malignancies 
receiving myelosuppressive anti-cancer therapy associated with 
a clinically significant incidence of febrile neutropenia 
Title of Study: 
A Phase III, Randomized, Multi-Centre, Open-Label, Fixed 
Dose, Neulasta® Active-Controlled Clinical Trial of F-627 in 
Women with Breast Cancer Receiving Myelotoxic 
Chemotherapy 
FDA IND # 
 






 
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A summary of the frequency of TEAEs from the Phase I study is presented in Table 2. The most 
frequently occurring TEAEs were back pain and headache. The frequencies of bone pain, pain in 
extremity and upper respiratory tract infection were greater than 33% in the treatment group. 
Meanwhile, other low-frequency TEAEs were reported, including abdominal pain, diarrhea, 
injection site pain, arthralgia, presyncope, etc. 
 
Table 2: TEAEs with Frequency >33% by Treatment Group 
Preferred Term 
 
(N=6) 
n (%) E 
 
(N=6) 
n (%) E 
 
(N=6) 
n (%) E 
 
(N=6) 
n (%) E 
 
(N=6) 
n (%) E 
Back pain 
2   (33.3%) 2 
1   (16.7%) 1 
4   (66.7%) 4 
4   (66.7%) 4 
4   (66.7%) 4 
Headache 
1   (16.7%) 2 
2   (33.3%) 2 
1   (16.7%) 1 
1   (16.7%) 2 
2   (33.3%) 2 
Bone pain 
0   (0.0%) 0 
2   (33.3%) 2 
0   (0.0%) 0 
3   (50.0%) 3 
0   (0.0%) 0 
Pain in extremity 
0   (0.0%) 0 
1   (16.7%) 1 
0   (0.0%) 0 
1   (16.7%) 1 
2   (33.3%) 2 
Upper respiratory 
tract infection 
0   (0.0%) 0 
0   (0.0%) 0 
0   (0.0%) 0 
2   (33.3%) 2 
2   (33.3%) 2 
Note: Data taken from Phase I clinical study report (GC-F-627-01). 
 
The Phase I clinical study in healthy male subjects demonstrated that F-627 was well tolerated at 
doses up to 
 by SC injection. Favorable PK properties and dose-dependent PD 
responses were demonstrated. The Phase I study results provide support for further clinical 
studies in chemotherapy-induced neutropenic cancer patients. 
The Phase II clinical trial, GC-627-02, was an open label, active-controlled, dose finding study 
that enrolled 232 women with breast cancer receiving myelotoxic chemotherapy. The primary 
objective of the study was to evaluate the efficacy of the F-627 given as a single dose (either 
 in each chemotherapy cycle in comparison to 
the standard dosing of Neulasta® (Neulastim®, pegfilgrastim; 6 mg; hereafter referred to as 
pegfilgrastim) in breast cancer subjects experiencing myelotoxic chemotherapy, either TC or 
TAC. Myelotoxicity in the Phase II study was defined by the duration of moderate neutropenia; 
the number of days in which the subject had an ANC <1.0 × 109/L during cycle 1 of their 
chemotherapy treatment. This, by definition, included grade 3 (moderate) and grade 4 (severe) 
neutropenia. The following conclusions were drawn from the study: 
Efficacy results of GC-627-02 
F-627 was not inferior to pegfilgrastim with respect to the duration of moderate to severe 
neutropenia at all doses. The duration and incidence of neutropenia and ANC profiles were 
comparable between pegfilgrastim and F-627 doses. 
A more myelotoxic chemotherapy regimen such as TAC provided a better model for evaluation 
of F-627 efficacy compared to pegfilgrastim. 
F-627 was as efficacious as pegfilgrastim in providing prophylactic neutrophil support in women 
with breast cancer undergoing myelotoxic chemotherapy. Further clinical studies with a larger 
patient population were recommended. 




 
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An integrated PK/PD modeling analysis was conducted using F-627 data from three human PK 
studies and two phase II human studies to justify the fixed dose regimen. The PD responses 
included depth of nadir for ANC, time to ANC recovery, and duration of neutropenia. The 
analysis demonstrated that administration of F-627 
 showed sufficient PD effect 
for either TAC or TC/EC chemotherapy types for depth of nadir and time to ANC recovery. A 
certain level of PD response was observed also of duration of neutropenia, especially for patients 
with TC/EC chemotherapy. Therefore, using a 
 as a therapeutic dose in a large 
confirmative trial is justified. 
2.3.3 Dosage Regimen 
The study drug, F-627, is a single dose administration that will be given on Day 2 (24 hours after 
chemotherapy treatment) of each cycle via a SC injection.   
2.4 Study Conduct 
The trial will be conducted in compliance with the trial protocol, ICH-GCP Guidelines, and the 
US Code of Federal Regulations, CFR Title 21 Food & Drug Administration. 
2.5 Study Population 
The population of patients enrolled in this study will be comprised of women, ≥18 years of age 
that have been diagnosed with Stage I-III invasive breast cancer and are scheduled to undergo 
neoadjuvant or adjuvant myelotoxic chemotherapy. Subjects will have an Eastern Cooperative 
Oncology Group (ECOG) performance status ≤2 with a white blood cell (WBC) count ≥4.0 × 
109/L, a platelet count ≥150 × 109/L and a base hemoglobin of ≥11.5 g/dL. Qualifying subjects 
must have adequate renal, hepatic, and cardiac function. Subjects will be excluded from the 
study if their disease has progressed while receiving a taxane regimen, if they have undergone 
radiation therapy within 4 weeks of enrollment, if they have received chemotherapy six months 
prior to screening, or if they have undergone a bone marrow or stem-cell transplantation. 
Subjects that have a history of prior malignancy other than breast cancer may enter the study 
provided the malignancy is in remission. Subjects that have used G-CSF within 6 weeks of the 
screening period are also excluded. Eligible subjects will meet the complete inclusion/exclusion 
criteria as presented in sections 5.1 and 5.2, respectively. 
3 TRIAL OBJECTIVES AND ENDPOINTS 
3.1 Primary Efficacy Objective 
The primary objective of the study is to evaluate the efficacy of F-627 given as a single fixed 
dose (20 mg) PFS as compared to Neulasta® standard dosing (6 mg) in the first chemotherapy 
cycle. 
3.2 Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the duration of grade 4 (severe) neutropenia, 
defined as the number of days in which the subject has had an ANC <0.5 × 109/L during cycle 1 
of their chemotherapy treatment.  




 
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4 TRIAL DESIGN AND RATIONALE  
4.1 Trial Design  
This Phase III, global, two arm, open label clinical study will randomize approximately 400 
subjects (approximately 200 per arm) with Stage I-III invasive breast cancer who are to receive 
neoadjuvant or adjuvant myelotoxic TC chemotherapy treatment (docetaxel + 
cyclophosphamide, 75 and 600 mg/m2, respectively). Subjects in this study will be those who are 
scheduled to undergo at least 4, 21-day cycles of chemotherapy treatment. Subjects maybe 
scheduled for more than 4 cycles of chemotherapy, however, study participation will be limited 
to a subject’s first 4 cycles. 
The primary endpoint of this study is based on the ANC laboratory measurements, which should 
remain free from bias. Due to the visual and packaging differences between the investigational 
drug, F-627, and the comparator, Neulasta®, this study is considered open-label. In order to 
provide for unbiased assessments of other efficacy and safety parameters, investigational drug 
injections must be administered by qualified study personnel separate from the investigator and 
study assessment personnel; the latter shall remain blinded to subject treatment assignment, 
permitting all assessments to be completed in a blinded, unbiased fashion.  
The patient population in this study is similar to studies conducted by Jones et al. and Kosaka et 
al. (3,4,5) Furthermore, studies by Kosaka et. al. and others have suggested that TC is a myelotoxic 
chemotherapy treatment that warrants prophylactic use of G-CSF for the prevention of febrile 
neutropenia.(5,6)  
Subjects in this study will be those who are scheduled to undergo at least 4, 21-day cycles of TC 
chemotherapy (docetaxel + cyclophosphamide, 75, and 600 mg/m2, respectively). Specifically, 
the Taxotere® brand of docetaxel will be used wherever possible to ensure treatment uniformity 
across the trial. In addition, the recommended steroid use the day before, the day of and the day 
after chemotherapy is dexamethasone at a dose level of no more than 8 mg BID. The design is 
similar to trials previously conducted with Neulasta® (Neulastim®, pegfilgrastim).(7,8,9)   
The screening period for this trial is approximately 17 days. During this time the subject will be 
consented and then evaluated for study eligibility via the study screening tests. The actual 
screening time may vary from subject to subject.  
Qualified subjects will be randomized to one of two arms in a 1:1 ratio using a central web based 
randomization system (IWRS) on Day 1 of the study, the day of chemotherapy administration for 
the first chemotherapy cycle. 
Approximately 24 hours after chemotherapy administration in each cycle (Day 2 of each cycle), 
subjects will be administered study drug according to their randomization arm: 
• Arm 1: F-627, 20 mg fixed dose pre-filled syringe. 
• Arm 2: 6 mg fixed dose Neulasta®. 
Clinical assessments will occur for all subjects during their screening period visit or visits (can 
occur from Day -17 to Day -1). Clinical assessments are cycle-specific upon study entry. 
ANC Assessment for Chemotherapy Cycle 1:   
For the first chemotherapy cycle, study subjects are required to return to the clinic to track ANC 
behavior post chemotherapy.   Subjects will return for cycle days 2-10, and each day thereafter 
until the subject’s ANC levels reach ≥2.0 × 109/L, post-nadir. Once a subject’s ANC is ≥2.0 × 


 
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109/L post-nadir, the subject will return three days later for their last cycle 1 ANC measurement. 
During a subject’s 1st chemotherapy cycle, local blood samples are to be drawn to monitor 
subject ANC levels for neutropenia during study visits and are to be used in instances where the 
central lab ANC results have been compromised (i.e. sample quality due to excessive shipping 
times).   
To begin full-dose chemotherapy on Day 1 of cycles 2 through 4 (i.e. Day 22 of the previous 
cycle), it is recommended that patients have a base hemoglobin of at least 11.5 g/dl, 
ANC >2.0 x 109/L and platelet count >100 x 109/L.   
ANC Assessment for Chemotherapy Cycles 2, 3, 4:   
For chemotherapy cycles 2, 3, 4, Subjects will return to the clinic after study drug administration 
for blood draws to track ANC behavior post chemotherapy. Subjects will return every other day 
starting from cycle day 3 to cycle day 11 and then every other day thereafter until the subject’s 
ANC level is ≥2.0 × 109/L. Once the subject’s ANC is ≥2.0 × 109/L post-nadir, the subject will 
return to the clinic three days later for the last ANC measurement for that chemotherapy cycle. 
Local blood samples maybe drawn to monitor subject ANC levels for neutropenia. 
Febrile neutropenia is defined as a single oral temperature of ≥38.3°C (101°F)  or a temperature 
of >38.0°C (100.4°F) sustained for >1 hour and ANC <0.5 x 109/L. If the ANC level of a subject 
is <0.5 for two consecutive visits, the subject must return the following day and then daily for an 
ANC blood draw until the ANC level is ≥2.0 × 109/L. 
Subjects will return for an End of Treatment (EOT) visit approximately 3 weeks and a follow up 
visit approximately 6 months post the final study drug administration. AEs recorded prior to and 
including the EOT visit will be followed to resolution or stabilization.  
The 6 month follow up visit will assess the subject’s disease progression/survival rate, and 
chemotherapy and G-CSF usage. Subjects will be asked to provide a blood sample for GCSF / F-
627 antibody testing. This visit will conclude the subject’s participation in the clinical trial. 
4.2 Rationale 
Recombinant human G-CSF (rhG-CSF) was developed and used to treat neutropenia, 
particularly for the management of neutropenia in patients with cancer.(10,11) The first generation 
rhG-CSF, filgrastim, received FDA approval in the US in 1991 for treating neutropenia.(12,13,14) 
The rhG-CSF produced in mammalian cells, lenograstim, is a glycosylated form that received 
approval in Europe in 1993 for treating neutropenia. Both filgrastim and lenograstim have a half-
life of approximately 3 hours and require daily administration.  
A new generation of rhG-CSF is a pegylated r-metHuG-CSF, pegfilgrastim, which received FDA 
approval in 2002.(15) Pegfilgrastim has an extended half-life of 30 to 80 hours and requires less 
frequent administration than filgrastim and lenograstim.(16,17,18) However, the addition of PEG 
appeared to reduce the affinity for receptor binding compared to parent rhG-CSF protein. The 
bioactivity of pegfilgrastim is reduced when compared to filgrastim. Filgrastim is dosed daily at 
300 µg for about 10 days (i.e., 3 mg total dose), while a higher total dose, 6 mg, of pegfilgrastim 
is required to achieve comparable clinical efficacy. 
Reducing the duration and severity of neutropenia following chemotherapy remains a challenge 
for cancer treatment.(19) The sponsor is investigating the efficacy of F-627, a dimeric rhG-CSF 
that is a stronger G-CSFR activator in treating neutropenia. F-627 may bring additional benefits 




 
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spermicide is also acceptable forms of contraception as long as they will be used continually 
throughout the duration of the trial. 
5.2 Subject Exclusion Criteria  
1. Subject is <18 years of age. 
2. Disease progression has occurred while receiving a taxane regimen. 
3. Subject has undergone radiation therapy within 4 weeks of enrollment. 
4. Subject has undergone bone marrow or stem-cell transplantation. 
5. Subject has a history of prior malignancy other than breast cancer that is NOT in remission. 
6. Subjects that have used G-CSF or any other drug that may potentiate the release of 
neutrophils (i.e., lithium) within 6 weeks of the screening period are excluded. 
7. Subject has had chemotherapy within 180 days of screening. 
8. Subject has documented congestive heart failure, cardiomyopathy or myocardial infarction 
by clinical diagnosis, electrocardiogram (ECG) test, or any other relevant test. 
9. History of alcohol or drug abuse that would interfere with the ability to be compliant with 
the study procedure. 
10. Unwillingness to participate in the study. 
11. Any underlying medical condition that, in the Investigator’s opinion, would make the 
administration of study drug hazardous to the patient or that would obscure the interpretation 
of adverse events. 
12. Receiving other investigational drugs or biologics within 1 month or five half lives of 
enrollment (if known), which ever is less. 
13. Any condition, which can cause splenomegaly. 
14. Chronic constipation or diarrhea, irritable bowel syndrome, inflammatory bowel disease. 
15. ALT, AST, alkaline phosphatase, total bilirubin ≥2.5x ULN. 
16. Subject with active infection, or known to be infected with chronic active Hepatitis B within 
the last 1 year (unless shown at the time of study entry to be Hepatitis B antigen negative), 
or having any history of Hepatitis C. 
17. Women who are pregnant or breast-feeding.  
18. Subject known to be seropositive for HIV, or who have had an AIDS defining illness or a 
known immunodeficiency disorder. 
19. Subject with a history of tuberculosis or exposure to tuberculosis. Patients that have received 
a prior chest X-ray for suspicion of tuberculosis are also excluded unless they have been 
confirmed to be PPD negative or they had latent tuberculosis that has been previously 
treated. 
20. Subjects with Sickle Cell disease 
21. Subjects with known hypersensitivity to E.coli-derived proteins‚ pegfilgrastim‚ filgrastim, or 
any other component of the study drug. 
5.3 Subject Withdrawal from Study 
5.3.1 Criteria for Subject Withdrawal 
1. Withdrawal of consent.  
2. Failure to comply with protocol requirements.  


 
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3. There are changes in the subject’s medical status that the Investigator believes would 
compromise patient safety or that would lead the Investigator to believe that it would be in 
the best interest of the subject to stop participation in the study.  
4. Subjects with a positive pregnancy test, such as a positive beta HCG. 
5. Death of the subject.  
5.3.2 Procedures for Subject Withdrawal 
At the time of withdrawal, subjects will be asked to complete all of the procedures that would 
normally be performed at the End of Study assessment. No other visits will be required, 
however, the subjects will be asked to attend their 6 month follow up visit dated from their last 
study drug administration. If the patient declines the 6 month follow up visit, no further 
evaluations are to be performed and no attempts should be made to contact the subject or collect 
additional data.  
5.3.3 Replacements for Withdrawn Subjects 
There will be no replacement of study subjects.   
5.3.4 Follow-Up of Withdrawn Subjects 
At the time of withdrawal from study, the reasons for the withdrawal should be ascertained and 
recorded in the study documentation.  
If the subject withdraws consent to continue in the study, the subject will be requested to 
participate in a post-treatment follow up phone call (28 days after the last dose). If the patient 
declines, no further evaluations are to be performed and no attempts should be made to contact 
the subject or collect additional data.  
If a subject does not return for scheduled visits, every effort should be made to re-establish 
contact. Attempts made to reach the subject should be clearly documented. If the subject cannot 
be contacted, every effort should be made to document subject outcome as far as possible.  
5.3.5 Documentation  
For any subject who withdraws, the date and the reason for the withdrawal must be recorded on 
the appropriate electronic Case Report Form (eCRF).  
6 TRIAL PROCEDURES 
See Section 18.1 and 18.2 (Study Flow Chart). 
6.1 Measures to Avoid Bias  
6.1.1 Randomization 
Eligible subjects in this study will be randomized to receive F-627 20 mg/dose or 6 mg/dose 
Neulasta® in 1:1 ratio. An interactive web-based response system (IWRS) with a 24-hour live 
support Helpdesk will be used for randomization in the study. Authorized study site personnel 
will access the randomization system using a user ID and password. Prior training and a user’s 
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Although the study is considered “open-label” due to differences in study drug presentations, the 
primary endpoint is based on a laboratory measurement (ANC) that is not subject to bias. As a 
result, study drug injections will be administered by qualified study personnel and investigators 
should remain blinded and perform all assessments without knowledge of treatment assignment. 
6.1.2 Simultaneous Utilization of All Arms 
Subjects will be randomized and stratified by country/region. All arms will be utilized 
concurrently. 
6.2 Trial Treatment and Dosage and Regimen of Investigational Products  
6.2.1 Treatment Dose 
Subjects will be dosed SC for each chemotherapy cycle with an F-627 PFS 20 mg/dose or 
6 mg/dose Neulasta®. Subjects will remain in their assigned treatment arm throughout the study.   
6.2.2 Description of the Dosage Form, Packaging and Labeling of the Investigational 
Product  
Each site will receive enough 20 mg F-627 drug kits for their subjects for the duration of the 
clinical trial. Each F-627 kit will contain one PFS of F-627 as a sterile, single use, preservative 
free solution for convenient SC injection. The clinical drug product should remain at a 
temperature between 2-8oC. Any temperature excursions from this storage condition should be 
recorded for time and duration and the study coordinator notified. 
The investigational drug product will be sent to the clinical sites in kits containing 1 uniquely 
labeled PFS each. Each kit will be labeled with the following information: 
Caution: New Drug -Limited by Federal (US) Law to Investigational Use. 
Sponsor’s name and address 
Drug Substance Name and Strength 
Protocol number  
Dosing instructions 
Storage conditions 
Lot Number 
Manufacturing Date 
 
Additional text will be added or removed from the label(s) as required by local regulations or 
provided in the subject’s information and informed consent document. 
6.2.3 Comparator Drug 
Commercially available U.S. licensed Neulasta® will be purchased and used as a comparator in 
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6.2.4 Investigational Drug Dose Schedule  
Dosing of study drug will commence on the second day of each chemotherapy cycle (up to 4 
cycles) the subject enters. The dosing should occur between 24 and 28 hours after the 
chemotherapy treatment is administered.  Study Drug is not be administered earlier then 24 hours 
post chemotherapy treatment. 
6.3 Duration of Subject Participation  
Prior to randomization, there is a screening period of up to 17 days for completion of consent 
form, collection of medical history, clinical signs and symptoms, and laboratory tests. The 
duration of subject participation once randomization has occurred is approximately 12 weeks, 
depending on the chemotherapy schedule deemed appropriate by the Investigator. Subjects 
completing the study will have their End or Treatment visit, approximately 3 weeks after their 
last study drug treatment, on Day 21 of their last chemotherapy cycle. For a subject with a 
17-day screening period that completes all four of the 21-day chemotherapy cycles, and the 
6 month follow up visit, the total participation will be 102 days. 
6.4 Hold and Stop Rules 
6.4.1 Stop Rules for Subjects (Study Drug Discontinuation) 
 
Any hospitalization due to a serious, uncontrolled infection requiring treatment with antibiotics, 
suspected drug related SAE may be cause for subjects to discontinue drug if the investigator 
feels it is appropriate.  Subjects with a demonstrated drug hypersensitivity will be discontinued 
from the trial.  In addition, the subject’s chemotherapy regimen may be discontinued at the 
Investigator’s discretion and thus there would be no additional study drug administration. 
6.4.2  End of Treatment and Follow-up Visits 
All subjects will receive an End of Treatment assessment on Day 84 (or 3 weeks after the 
patient’s last dose of investigational agent). All AEs will be followed until stabilization or 
resolution. Note: these dates are approximate as they are dependent upon an individual’s 
chemotherapy treatment schedule. All subjects will be asked to return approximately 6 months 
after their last study drug administration. This will conclude the subject’s participation in the 
clinical trial. 
6.5 Accountability Procedures 
Study medication will be shipped to each institution at the time of site initiation. The IWRS will 
be used to monitor the inventory level of investigational drug supply at clinical sites. The 
Investigator is also responsible for monitoring the inventory of medication supplies, to ensure 
sufficient supply for the site. The study monitors will also verify the drug accountability during 
each monitoring visit. At the end of the study, all study drug supplies will be returned to the 
Sponsor/designee by the study monitor for each site, or destroyed on-site per local documented 
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6.6 Electronic Case Report Forms   
Each site is responsible for collecting and maintaining the source documentation describing the 
clinical information. eCRFs are to be completed using the electronic data capture (EDC) system 
iDataFax 2014.1.1. Sites will receive training and guidelines for appropriate eCRF completion.  
All eCRFs should be completed by designated, trained examining personnel or the study 
coordinator as appropriate, and should be completed in a timely manner for each enrolled 
subject. It is expected that sites will enter data as per the industry time standard, 5 business days 
after the subject visit. The completed eCRFs are the sole property of the trial Sponsor and should 
not be made available in any form to third parties, except for authorized representatives of the 
trial Sponsor or appropriate regulatory authorities, without written permission from the Sponsor. 
It is the Principal Investigator's responsibility to ensure completion and to review and approve all 
eCRFs. eCRFs must be signed by the Principal Investigator or by a sub-Investigator who has 
official authorization in accordance with local regulatory authorities. These signatures serve to 
attest that the information contained on the eCRFs is correct and complete. At all times, the 
Principal Investigator has final personal responsibility for the accuracy and authenticity of all 
clinical and laboratory data entered on the eCRFs. Subject source documents are the physician's 
subject records maintained at the trial sites. The information collected on the eCRFs must match 
the subject source documents. 
7 TREATMENT OF SUBJECTS 
7.1 Dosing 
SC administration of study drug will occur on Day 2 of each chemotherapy cycle that the subject 
undergoes (up to 4 cycles). See Appendix sections 18.1 and 18.2 for specific details. 
7.2 Concomitant Medications  
Concomitant medications are permitted as deemed appropriate by the investigator. All 
concomitant medications and the details of their prescription(s) are to be recorded in the 
appropriate eCRF. 
7.3 Approved Medications 
Any FDA-approved prescription medication may be given as needed, including those necessary 
to treat symptoms. Subjects experiencing febrile neutropenia may be treated with antibiotics and 
any medications as deemed necessary as per local standard of care and as the supervising 
investigator determines appropriate.   
7.4 Medications Not Permitted 
F-627 is similar to Neulasta® (Neulastim®, pegfilgrastim) and stimulates neutrophil production 
in vivo. No formal drug interaction studies have been performed with Neulasta® (Neulastim®, 
pegfilgrastim), so there are no drugs specifically contraindicated for this study. G-CSF use 
outside of the study drug administrations are not permitted during the study, however, if the 
subject experiences prolonged severe neutropenia (>6 days), the subject may be treated with a 
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appropriate, with appropriate documentation as a concomitant medications. Drugs such as 
lithium may potentiate the release of neutrophils and thus are not permitted in this study. 
7.5 Compliance 
Study drug administration compliance will be monitored by reviewing the study medication 
accountability and inventory logs. Source documentation will be reviewed to verify protocol 
compliance throughout the duration of the study. 
8 ASSESSMENT OF EFFICACY  
8.1 Efficacy Parameters 
Efficacy parameters will include the duration of grade 4 neutropenia (ANC <0.5 x 109/L) 
observed in all chemotherapy cycles as determined by ANC levels derived from daily blood 
sampling. Central lab results will be used for any statistical analysis performed in this trial to 
ensure consistent measurements throughout the duration of the clinical trial. Local lab ANC 
results may be used for statistical analysis only when the central lab results are absent. 
9 ASSESSMENT OF SAFETY  
9.1 Safety Parameters 
9.1.1 Standard Safety Parameters 
Standard safety parameters include hematology, blood chemistry and urinalysis parameters, vital 
signs, physical examination, and symptom/toxicity assessment. The National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03 will be used to grade 
potential AEs.  
Local blood samples maybe used to determine the status of a subject’s ANC level for local safety 
monitoring and evaluation.   
9.2 The Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
9.2.1 Medical History and Clinical Signs and Symptoms  
A medical history is collected at the screening visit. Clinical signs and symptoms will be taken at 
each scheduled visit during which AE data will be collected. If other unscheduled activities are 
performed, such as physical examination or laboratory studies, the results must be provided on 
the eCRFs. 
9.2.2 Physical Examination 
A physical examination will take place at screening and at each clinical visit as presented in the 
Study Flow chart (section 18.2). Any change from baseline will be evaluated and assessed by the 
Investigator. An abbreviated physical exam may be completed at any visit as deemed appropriate 
by medical staff. Results of such abbreviated physical exams must be included in the eCRFs. 


 
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9.2.3 Reporting 
For each subject, all clinical laboratory assessments will be reported on an eCRF. 
9.3 Procedures for Eliciting Reports of and Recording and Reporting Adverse 
Events and Intercurrent Illnesses 
At each visit, a history of any AEs occurring since the last visit needs to be collected. Also, 
specimens are collected for specified laboratory tests as needed and results should be reviewed. 
Physical examinations are performed at each clinical visit as presented in the Study Flow chart 
(section 18.2) and more frequently as clinically indicated.  
9.4 Type and Duration of Follow-Up of Subjects after Adverse Events 
Study subjects will have their EOT visit on Day 21 of their 4th chemotherapy cycle. Subjects 
will be queried for identification of AEs. Subsequent to the AE follow-up, subjects who 
discontinue due to febrile neutropenia will be followed up for an additional 30 days to identify 
further febrile neutropenia events or severe neutropenia (defined as ANC <0.5 x 109/L) with 
duration >2 days. Any grade 3 or 4 AEs or SAEs should be followed up until they have resolved 
or stabilized. The sponsor must be advised of all grade 3 or 4 AEs within one week of their 
identification and of all SAEs within 24 hours of identification. Subjects will be followed until 
the AE resolves or stabilizes.   
9.5 Defining, Grading and Reporting Adverse Events 
9.5.1 Adverse Events 
All AEs, whether observed by researchers or reported by subjects, regardless of treatment group 
or suspected causal relationship to the investigational product(s), will be recorded on the AE 
page(s) of the eCRF.  
For all AEs, the Investigator must obtain adequate information to determine the cause and 
outcome of the AE, and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Generon and its designated representative (see Section 9.5.9). 
The Investigator is required to assess the causality and indicate that assessment on the eCRF. 
Follow-up of the AE, after the date of therapy discontinuation, is required until the AE or 
subsequent resulting AEs attributed to an ongoing AE resolves or stabilizes at a level acceptable 
to the Investigator and the Generon clinician and safety officer. 
9.5.2 Definition 
An adverse event (AE) is any occurrence or worsening of an undesirable or unintended sign, 
symptom (including an abnormal laboratory finding), or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
Worsening of underlying disease will not be considered to be an AE, since it will be classified as 
a treatment failure. Pregnancy will not be considered to be an AE, but will be collected 
separately. However, if the resultant child has a birth defect, this will be considered an SAE. 
Throughout the study, the Investigator must record all AEs on the eCRF AE pages, regardless of 
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subjects with AEs appropriately and observe them at suitable intervals until the events resolve or 
stabilize. 
AEs can be discovered by observing the patient, questioning the patient objectively, and/or 
receiving an unsolicited complaint from the patient. 
AEs will be collected from the start of the study medication until study termination. AEs that are 
unresolved at the time of study termination will be followed until they resolve or stabilize. 
9.5.3 Serious Adverse Events 
Serious adverse events (SAE) are defined as any AE occurring at any dose that suggests a 
significant hazard, contraindication, side effect, or precaution. This includes, but may not be 
limited to any of the following events: 
1. Death: A death occurring during the study, or which comes to the attention of the 
Investigator during the protocol-defined follow-up after the completion of therapy, must be 
reported whether or not considered treatment-related. 
2. Life-threatening: Any adverse therapy experience that places the subject, in the view of the 
Investigator, at immediate risk of death from the reaction as it occurred. 
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant disability/incapacity. 
5. Congenital anomaly/birth defect. 
6. Spontaneous abortion or death of the infant within 1 month of birth. 
7. An event that required intervention to prevent permanent impairment or damage.  
8. An important medical event that does not result in death, that may not necessarily be life 
threatening and that does not require hospitalization may still be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
 
Pregnancy is NOT an SAE, unless it is an ectopic pregnancy. Depending on the outcome of a 
pregnancy, an SAE may not need to be submitted (see section 9.5.5). 
Hospitalization for observational purposes, study visit convenience, or scheduled procedures are 
not to be considered SAEs. Any AEs experienced during this “observational” hospitalization will 
not be considered SAEs unless, in the opinion of the Investigator, they meet one of the above-
specified SAE criteria; in which case, the AE is to be reported as an SAE. 
SAEs will be collected from the time of randomization until 30 days after the last study drug 
administration or 30 days after premature withdrawal of a subject from the trial. 
If an event meets any of the criteria listed above, it must be reported as an SAE regardless of its 
presumed relation to the study drug. 
9.5.4 Grading Adverse Events 
Toxicity grades are assigned by the study site to indicate the severity of AEs occurring in study 
participants using the NCI-CTCAE v4.03 grading system. The purpose of using the NCI-CTCAE 
system is to provide a standard language to describe toxicities, to facilitate tabulation and 


 
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analysis of the data, and to facilitate the assessment of the clinical significance of all AEs. AEs 
should be recorded and graded 1 to 5 according to the NCI-CTCAE grades provided below: 
 
Grade 1 = Mild AE 
 
Grade 2 = Moderate AE 
 
Grade 3 = Severe and undesirable AE 
 
Grade 4 = Life-threatening or disabling AE 
 
Grade 5 = Death 
If an AE term cannot be found in the NCI-CTCAE, the AE should be graded based on the 
verbiage provided for the grades above. 
9.5.5 Exposure in Utero 
For investigational products within clinical trials and for marketed products, an exposure in-utero 
(EIU) occurs if a female becomes, or is found to be, pregnant either while receiving or having 
been exposed to (e.g., environmental) an investigational medication or product, or if the female 
becomes, or is found to be, pregnant after discontinuing and/or being exposed to the 
investigational medication or product. 
If any trial subject becomes or is found to be pregnant while receiving an investigational 
medication/product, the Investigator must submit this information to the Generon Safety Officer 
or Sponsor designee using the paper Pregnancy Report Form within 24 hours of awareness of the 
pregnancy. This must be done irrespective of whether an AE has occurred. The information 
submitted should include the anticipated date of delivery (see below for information related to 
induced termination of pregnancy).  
The Investigator will follow the subject until completion of the pregnancy or until pregnancy 
termination (i.e., induced abortion) and then notify the Generon Medical Officer or Sponsor’s 
designee of the outcome. The Investigator will provide this information as a follow up to the 
initial Pregnancy Report Form. The reason(s) for an induced abortion should be specified. A 
Pregnancy report should not be created when an ectopic pregnancy report is received since this 
pregnancy is not usually viable. Rather, an SAE Report Form should be completed with the 
event of ectopic pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly, including that found in an 
aborted fetus, stillbirth or neonatal death), the Investigator should follow the procedures for 
reporting SAEs. 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(i.e., no minimum follow-up period of a presumably normal infant is required before a 
Pregnancy Report Form can be completed). The “normality” of an aborted fetus can be assessed 
by gross visual inspection, unless pre-abortion test findings are suggestive of a congenital 
anomaly. 
Additional information about pregnancy outcomes that are classified as SAEs are as follows:  
• “Spontaneous abortion” includes miscarriage and missed abortion. 


 
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• All neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 1 month that the Investigator assesses 
as possibly related to the in utero exposure to the investigational medication should be 
reported. 
9.5.6 Relationship to Study Therapy 
The relationship between an AE and an investigational product is determined by the site 
Investigator and recorded on the appropriate eCRF and/or SAE Reporting Form. The CTCAE 
provides the following descriptors and definitions (see Table 3). 
The Investigator’s determination of drug-relatedness (attribution) for each AE should be 
recorded in the source documentation.  
For additional information, please consult the NCI-CTCAE v 4.03 and the Common Toxicity 
Criteria Document at the following URL: http://ctep.cancer.gov/reporting/ctc.html.  
Table 3: Attribution of Adverse Events 
“Unrelated” Category Code: 
Code 
Descriptor 
Definition 
1 
Unrelated 
The adverse event is clearly not related to the investigational agent(s). 
2 
Unlikely 
The adverse event is doubtfully related to the investigational agent(s). 
“Related” Category Codes:1 
Code 
Descriptor 
Definition 
3 
Possible 
The adverse event may be related to the investigational agent(s). 
4 
Probable 
The adverse event is likely related to the investigational agent(s). 
5 
Definite 
The adverse event is clearly related to the investigational agent(s). 
1 
For regulatory reporting purposes, only SAEs that meet the definition of “related” and are unexpected will 
be reported in an expedited manner. 
 
9.5.7 Abnormal Laboratory Findings 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE are as follows:  
1. Test result is associated with accompanying symptoms, and/or 
2. Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
3. Test result leads to a change in trial dosing, discontinuation from the study, or significant 
additional concomitant drug treatment or other therapy, and/or 
4. Test result is considered to be an AE by the Investigator or Sponsor. 
 
An abnormal test result, even if repeated, does not constitute an AE in the absence of any of the 
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reporting as an AE. Local lab results may be used to monitor subject safety during the course of 
the study and are to be reported when associated with AEs. 
The NCI-CTCAE v4.03 will be used to grade the severity of laboratory abnormalities. 
9.5.8 Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
trial subject. In addition, each trial subject will be questioned about AEs at each clinic visit. The 
question asked will be “Since your last clinic visit have you had any health problems?” or a 
similar question.  
9.5.9 Reporting Requirements (Serious and Non-Serious) 
Each AE is to be classified by the Investigator as serious or non-serious. This classification 
determines the reporting procedures to be followed. If an SAE occurs, expedited reporting will 
follow local and international regulations. 
SAEs are reportable from the time that the subject is randomized in the clinical trial up to and 
including 30 calendar days after the last administration of the investigational product. Any SAE 
occurring more than 30 calendar days after completion of the study must be promptly reported if 
a causal relationship to study drug is suspected.  
If an SAE occurs, the Generon Safety Officer and/or his/her agent are to be notified 
within24 hours of awareness of the event by the Investigator. In particular, if the SAE is fatal or 
life-threatening, notification must be made to the Generon Safety Officer or his/her agent 
immediately, irrespective of the extent of available AE information. This time frame also applies 
to additional new information (follow-up) on previously forwarded SAE reports. 
In the rare event that the Investigator does not become aware of the occurrence of a SAE 
immediately (e.g., if an outpatient trial subject initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
For all SAEs, the Investigator is obligated to provide information to the Generon Safety Officer 
and his/her agent in accordance with the time frames for reporting specified above. In addition, 
the Generon study clinician or the Generon Safety Officer may request an Investigator obtain 
specific follow-up information in an expedited fashion. This information may be more detailed 
than that captured on the AE eCRF. This will include a description of the AE in sufficient detail 
to allow for a complete medical assessment of the case and independent determination of 
possible causality. Information on other possible causes of the event, such as concomitant 
medications and illnesses, must be provided. In the case of a subject death, a summary of 
available autopsy findings must be submitted as soon as possible to the Generon Safety Officer 
and his/her designated representative. 
The Investigator’s causality assessment must be included in all reports of SAEs. An 
Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE. If the Investigator’s 
final determination is that causality is unknown and the Investigator cannot determine whether 
the event is related to study drug, then the event will be considered “related to study drug” for 
reporting purposes. If the Investigator's causality assessment is "unknown but not related to study 
drug", this should be clearly documented on study records. In addition, if the Investigator 


 
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determines the AE is associated with trial procedures, the Investigator must record this causal 
relationship in the source documents and eCRF, as appropriate, and report such an assessment in 
accordance with the SAE reporting requirements.  
All AEs will be reported on the AE page(s) of the eCRF. It should be noted that the form for 
collection of SAE information is not the same as the AE eCRF. Where the same data are 
collected, the forms must be completed in a consistent manner. For example, the same AE term 
should be used on both forms/eCRFs. AEs should be reported using concise medical terminology 
as defined in the CTCAE short names on the eCRFs, as well as on the form for collection of SAE 
information. 
Non-serious AEs are to be reported on the AE page of the eCRFs, which are to be submitted to 
Generon as specified in the AE report submission procedure for this protocol.  
If a subject begins a new therapy, the AE reporting period will end at the time that the new 
treatment is started. A death must be reported if it occurs within 30 days after the date of last 
dose of investigational product, irrespective of any intervening treatment. 
10 STATISTICAL ANALYSIS 
Detailed methodology for summary and statistical analyses of the data collected in this trial will 
be documented in a Statistical Analysis Plan (SAP), which will be signed and maintained by the 
Sponsor. This document will expand upon and may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition and/or its analysis will also 
be reflected in a protocol amendment. 
10.1 Study Endpoints 
10.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the duration of grade 4 (severe) neutropenia, 
defined as the number of days in which the subject has had an ANC <0.5 × 109/L during cycle 1 
of their chemotherapy treatment.   
10.1.2 Secondary Efficacy Endpoints 
The secondary endpoints are: 
• The duration of use of intravenous (IV) antibiotics (total across all chemotherapy cycles). 
• The duration of hospitalization for febrile neutropenia or any infection (total across all 
chemotherapy cycles). 
• The incidence of febrile neutropenia, considering all chemotherapy cycles. Febrile 
neutropenia is defined as a single oral temperature of ≥38.3°C (101°F) or a 
temperature of >38.0°C (100.4°F) sustained for >1 hour and ANC <0.5 x 109/L on the 
same day.  
• The incidence of grade 4 neutropenia for chemotherapy cycle 1. 
• The incidence of use of IV antibiotics, considering all chemotherapy cycles. 
• The incidence of hospitalization for febrile neutropenia or any infection, considering all 
chemotherapy cycles. 






 
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assumptions. Assuming a 10% drop-out rate, a total sample size of 386 should be randomized 
across both treatment arms. 
10.3 Criteria for Termination and Sponsor Discontinuation Criteria 
Premature termination of this clinical trial may occur because of a regulatory authority decision, 
change in opinion of the Institutional Review Board (IRB)/Independent Ethics Committee (IEC), 
drug safety problems, or at the discretion of Generon. In addition, Generon retains the right to 
discontinue development of F-627 at any time. 
Generon reserves the right to discontinue the trial prior to inclusion of the intended number of 
subjects, but intends only to exercise this right for valid scientific or administrative reasons. 
After such a decision, the Investigator must contact all participating subjects within a time period 
set by Generon. As directed by Generon, all trial materials must be collected and all eCRFs 
completed to the greatest extent possible. 
10.4 Procedure for Accounting for Missing, Unused and Spurious Data 
There will be no imputation of the primary endpoint data in the PP analysis. However, data 
imputation methods will be applied to missing values in the ITT analysis. Imputation methods 
will be described in the SAP. 
10.5 Procedure for Reporting Deviations from the Original Statistical Plan and 
Justification 
The principal features of the design of this study and of the plan for statistical analysis of the data 
are outlined in this protocol and SAP. Any changes in the principal features would require a 
protocol or SAP amendment. These changes will be described in the final clinical study report. 
10.6 Selection of Subjects Included in the Analysis 
10.6.1 Safety Analyses Set  
All enrolled subjects receiving any study treatment will be included in the Safety Analysis  
Set, which will be used for all safety analyses. The data in the Safety Analysis Set will be 
analyzed according to the treatment received. 
10.6.2 Intent to Treat Analysis Set  
All randomized subjects will be included in the ITT Analysis Set. Following the ITT principle in 
the ICH E9 guidance, the data of all the participants in the ITT Analysis Set will be analyzed 
according to their randomized treatment. The ITT Analysis Set will be used as the primary 
Analysis Set in the non-inferiority efficacy analysis and for all secondary efficacy endpoints. 
10.6.3 Per Protocol Analysis Set  
All subjects from the ITT Analysis Set who received study treatment, who are eligible and 
compliant, and without major protocol deviations during the first cycle of treatment will be 
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the PP Analysis Set will be defined by the Sponsor in a blinded manner prior to database lock. 
The PP Analysis Set will be used for sensitivity analysis of the primary endpoint and all 
secondary endpoints. Major protocol deviations include, but are not limited to, receiving 
incorrect treatment, or non-compliance to ANC collection in the first 12 days of cycle 1 that may 
affect the primary endpoint. 
10.7 Six(6)-month Long-term Follow-up Analysis  
Database lock and data analyses will occur after all subjects have completed the End-of-
Treatment visit (21 days after the last dose of study drug), with the exception of the long-term 
follow-up visit scheduled for 6 months after last dose of study drug. Long-term follow-up visit 
will be analyzed and reported subsequently once all data for these assessments are completed. 
11 DIRECT ACCESS TO SOURCE DOCUMENTS 
The Principal Investigator and the Investigator’s institution must permit trial-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to source 
data/documents. 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
During trial conduct, Generon or its agents will conduct periodic monitoring visits to ensure that 
the protocol and GCP’s are being followed. The monitors may review source documents to 
confirm that the data recorded on eCRFs are accurate. The investigators and institutions will 
allow Generon’s monitors or its agents and appropriate regulatory authorities direct access to 
source documents to perform this verification. 
The trial sites may be subject to review by the institutional review board (IRB)/independent 
ethics committee (IEC), quality assurance audits performed by Generon and/or inspection by 
appropriate regulatory authorities from the US or other countries. 
Investigator(s) and their relevant personnel must be available during the monitoring visits and 
audits or inspections. Sufficient time must be devoted to these inspections. 
The Investigator is required to keep accurate records to ensure the conduct of the study is fully 
documented. The Investigator is required to ensure that all electronic Case Report Forms are 
complete, accurate and legible for every subject entered in the trial. 
The Sponsor is responsible for regular inspection of the conduct of the trial, for verifying 
adherence to the protocol, and for confirming the completeness, consistency and accuracy of all 
documented data. 
13 ETHICS 
13.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the Investigator to obtain prior approval of the trial protocol, protocol 
amendments, informed consent forms, and other relevant documents, e.g., advertisements, if 
applicable, from the IRB/IEC. All correspondence with the IRB/IEC should be retained in the 
Investigator File. Copies of IRB/IEC approvals should be forwarded to Generon or its designees. 


 
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The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the Investigator must notify the IRB/IEC and Generon or its designees in writing within 
five working days after the implementation. 
13.2 Ethical Conduct of the Trial 
The trial will be performed in accordance with the protocol, ICH-GCP guidelines, and applicable 
local regulatory requirements and laws. 
13.3 Patient Information and Consent 
The informed consent form must be agreed to by Generon and the IRB/IEC and must be in 
compliance with ICH-GCP, local regulatory requirements, and legal requirements. 
The Investigator must ensure that each trial subject, or his/her legally acceptable representative, 
is fully informed about the nature and objectives of the trial and possible risks associated with 
participation. The Investigator will obtain written informed consent from each subject or the 
subject's legally acceptable representative before any study-specific activity is performed. The 
informed consent form used in this trial, and any changes made to it during the course of the 
trial, must be approved by both the IRB/IEC and Sponsor before use. The Investigator will retain 
a copy of each subject's signed consent form. 
A Sponsor recommended sample informed consent form will be provided to the investigational 
site as a separate document. Modifications to the consent required by ethics committee/IRB 
should be reviewed by the Sponsor. 
14 DATA HANDLING AND RECORD KEEPING 
14.1 Electronic Case Report Forms (eCRFs) 
Each site is responsible for collecting and maintaining the source documentation describing the 
clinical information.  
eCRFs are to be completed using the EDC system iDataFax 2014.1.1. Sites will receive training 
and guidelines for appropriate eCRF completion.  
All eCRFs should be completed by designated, trained examining personnel or the study 
coordinator as appropriate, and should be completed in a timely manner for each enrolled 
subject. It is expected that the eCRFs will be completed within 5 days of a subject’s visit, as per 
the industry time standard. The completed eCRFs are the sole property of the trial Sponsor and 
should not be made available in any form to third parties, except for authorized representatives of 
the trial Sponsor or appropriate regulatory authorities, without written permission from the 
Sponsor. 
It is the Principal Investigator's responsibility to ensure completion and to review and approve all 
eCRFs. eCRFs must be signed by the Principal Investigator or by a sub-Investigator who has 
official authorization in accordance with local regulatory authorities. These signatures serve to 
attest that the information contained on the eCRFs is correct and complete. At all times, the 
Principal Investigator has final personal responsibility for the accuracy and authenticity of all 
clinical and laboratory data entered on the eCRFs. Subject source documents are the physician's 


 
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subject records maintained at the trial sites. The information collected on the eCRFs must match 
the subject source documents. 
14.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or Generon, the Investigator 
agrees to keep complete records, including the identity of all participating subjects (sufficient 
information to link records, e.g., eCRFs and hospital records), all original signed informed 
consent forms, copies of all eCRFs, source documents, and detailed records of treatment 
disposition. The records must be retained by the Investigator according to ICH and local 
regulations, as well as the Clinical Study Agreement. 
If the Investigator relocates, retires, or for any reason withdraws from the trial, Generon should 
be notified in advance. The trial records must be transferred to an acceptable designee, such as 
another Investigator, another agreed-upon institution, or to Generon. The Investigator must 
obtain written permission from Generon before disposing of any records, even if retention 
requirements have been met. 
15 FINANCING AND INSURANCE 
The Sponsor, Generon, will ensure sufficient funding for completion of this trial and will provide 
adequate insurance for trial conduct.  
16 PUBLICATION POLICY 
Publication of study results is discussed in the Clinical Study Agreement. All publications to be 
submitted to scientific journals or presentations to be given at scientific meetings must be 
submitted to Generon (Shanghai) at least one month prior to submission. Planned presentations 
must include all slides. This includes presentations given at the presenters’ own institution (such 
as Grand Rounds). However, presentations given to the study team are not required to be 
approved in advance. 


 
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17 REFERENCES  
1. Hu,Z., Huang,Z.H., Cen,X.B., Wang,T., Zhuang,K., Zhang,D.P., Sun,N.C., Sun,R.Y., 
Wang,L., Huang,Y.L. et al 2010. F-627, a G-CSF Dimer, Stimulated a More Rapid 
Neutrophil Recovery In Cyclophosphamide-Treated Monkeys Compared to Monomer rhG-
CSFs. In 52nd ASH Annual Meeting and Exposition. 
2. Tang,T., Hodsman,G.P., Huang,Z.H., Sun,R.Y., Sun,N.C., Huang,Z.H., and Yan,X.Q. 2011. 
Pharmacokinetic and pharmacodynamic properties of F-627, a G-CSF dimer, in healthy 
male volunteers . In ISEH 2011 Annual Meeting. 
3. Jones,R.L., Walsh,G., Ashley,S., Chua,S., Agarwal,R., O'Brien,M., Johnston,S., and 
Smith,I.E. 2009. A randomised pilot Phase II study of doxorubicin and cyclophosphamide 
(AC) or epirubicin and cyclophosphamide (EC) given 2 weekly with pegfilgrastim 
(accelerated) vs 3 weekly (standard) for women with early breast cancer. Br. J. Cancer. 
100:305-310. 
4. Jones,S.E., Savin,M.A., Holmes,F.A., O'Shaughnessy,J.A., Blum,J.L., Vukelja,S., 
McIntyre,K.J., Pippen,J.E., Bordelon,J.H., Kirby,R. et al 2006. Phase III trial comparing 
doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant 
therapy for operable breast cancer. J. Clin. Oncol. 24:5381-5387. 
5. Kosaka,Y., Rai,Y., Masuda,N., Takano,T., Saeki,T., Nakamura,S., Shimazaki,R., Ito,Y., 
Tokuda,Y., Tamura,K. 2015. Phase III placebo-controlled, double-blind, randomized trial of 
pegfilgrastim to reduce the risk of febrile neutropenia in breast cancer patients receiving 
docetaxel/cyclophosphamide chemotherapy. Support Cancer Care. 23:1137-1143. 
6. Ngamphaiboon N, O’Connor TL, Advani PP, Levine EG, and Kossoff EB. Febrile 
neutropenia in adjuvant docetaxel and cyclophosphamide (TC) with prophylactic 
pegfilgrastim in breast cancer patients: a retrospective analysis. Med Oncol. 29:1495-1501. 
7. Holmes,F.A., Jones,S.E., O'Shaughnessy,J., Vukelja,S., George,T., Savin,M., Richards,D., 
Glaspy,J., Meza,L., Cohen,G. et al 2002. 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. 13:903-909. 
8. Holmes,F.A., O'Shaughnessy,J.A., Vukelja,S., Jones,S.E., Shogan,J., Savin,M., Glaspy,J., 
Moore,M., Meza,L., Wiznitzer,I. et al 2002. Blinded, randomized, multicenter study to 
evaluate single administration pegfilgrastim 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. 20:727-731. 
9. Green,M.D., Koelbl,H., Baselga,J., Galid,A., Guillem,V., Gascon,P., Siena,S., Lalisang,R.I., 
Samonigg,H., Clemens,M.R. et al 2003. A randomized double-blind multicenter phase III 
study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients 
receiving myelosuppressive chemotherapy. Ann. Oncol. 14:29-35. 
10. Glaspy,J.A., and Golde,D.W. 1992. Granulocyte colony-stimulating factor (G-CSF): 
preclinical and clinical studies. Semin. Oncol. 19:386-394. 
11. Smith,T.J., Khatcheressian,J., Lyman,G.H., Ozer,H., Armitage,J.O., Balducci,L., 
Bennett,C.L., Cantor,S.B., Crawford,J., Cross,S.J. et al 2006. 2006 update of 
recommendations for the use of white blood cell growth factors: an evidence-based clinical 
practice guideline. J. Clin. Oncol. 24:3187-3205. 


 
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12. Morstyn,G., Lieschke,G.J., Sheridan,W., Layton,J., Cebon,J., and Fox,R.M. 1989. Clinical 
experience with recombinant human granulocyte colony-stimulating factor and granulocyte 
macrophage colony-stimulating factor. Semin. Hematol. 26:9-13. 
13. Morstyn,G., Campbell,L., Duhrsen,U., Souza,L.M., Alton,N.K., Villeval,J.L., Nicola,N.A., 
Boyd,A.W., Kannourakis,G., Cebon,J. et al 1988. Clinical studies with granulocyte colony 
stimulating factor (G-CSF) in patients receiving cytotoxic chemotherapy. Behring Inst. 
Mitt.234-239. 
14.  Neupogen (filgrastim) prescribing information. http://www.neupogen.com/pi.html. 
15.  Neulasta® Product information. www.neulasta.com/patient/neulasta-product-
information.html. 
16. Lyman,G.H. 2005. Pegfilgrastim: a granulocyte colony-stimulating factor with sustained 
duration of action. Expert. Opin. Biol. Ther. 5:1635-1646. 
17. Molineux,G. 2004. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, 
Neulasta). Curr. Pharm. Des. 10:1235-1244. 
18. Roskos,L.K., Lum,P., Lockbaum,P., Schwab,G., and Yang,B.B. 2006. 
Pharmacokinetic/Pharmacodynamic Modeling of Pegfilgrastim in Healthy Subjects. J. Clin. 
Pharmacol. 46:747-757. 
19. Sierra,J., Szer,J., Kassis,J., Herrmann,R., Lazzarino,M., Thomas,X., Noga,S.J., Baker,N., 
Dansey,R., and Bosi,A. 2008. A single dose of pegfilgrastim compared with daily filgrastim 
for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute 
myeloid leukemia: results from a randomized, double-blind, phase 2 trial. BMC. Cancer. 
8:195-204. 
20. Generon (Shanghai) Corporation. Statistical Report on an Indirect Meta-analysis for the 
Establishment of Efficacy Bounds for the Non-inferiority Testing of F-627 against 
Neulasta® for the Control of Chemotherapy-induced Neutropenia. August 2016. 
 


 
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18 APPENDICES  
18.1 Trial Procedures and Activities 
Pregnancy tests will be performed at screening (serum). 
 
Initial Screen (within 17 days of randomization): 
 
• 
Informed Consent is signed 
• 
Medical cancer history 
• 
Listing of all treatments and current therapies over the past three months and any 
chemotherapy regimens in the past 1 year from the date of informed consent. 
• 
Physical examination 
• 
Height and body weight 
• 
Body temperature 
• 
Vital Signs (blood pressure (BP) and heart rate) 
• 
Complete Blood Count (CBC) with Differentials  
• 
Blood chemistry (Sodium, Potassium, blood urea nitrogen (BUN), Serum Creatinine, 
Chloride, Bicarbonate, Calcium, Phosphorus, Glucose, Bilirubin, ALT, AST, 
Alkaline Phosphatase, GGT, LDH) 
• 
Serum pregnancy test as appropriate  
• 
Urinalysis  
• 
Abdominal ultrasound (focused on the area where the spleen resides) 
• 
ECG-12 lead 
• 
Collection of baseline conditions 
• 
Baseline or entry medications  
 
Study Days 1, 22*, 43*, 64* (chemotherapy administration day) 
 
• 
Body weight 
• 
Physical examination  
• 
Collect vital signs (BP and heart rate) 
• 
Body Temperature 
• 
CBC with Differentials 
• 
Serum draws for GCSF/F-627 antibodies assay. 
• 
Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, 
Bicarbonate, Calcium, Phosphorus, Glucose, Bilirubin, ALT, AST, Alkaline 
Phosphatase, GGT, LDH) 
• 
Urinalysis 
• 
Collection of AEs 
• 
Concomitant medications  
 
Administration of chemotherapy should be upon completion of the above tests. 
Randomization should occur after chemotherapy has been administered. 


 
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• 
Randomization (For cycle 1 ONLY, after chemotherapy administration) 
 
*  Actual study days may vary and are dependent upon each subject’s chemotherapy 
schedule as determined by the Investigator. 
 
Day 2 of Each Chemotherapy Cycle (corresponds to study days 2, 23*, 44*, 65*):  
 
• 
Body temperature 
• 
Collect vital signs (BP and heart rate) 
• CBC with Differentials, local and central lab sample, blood smear sample 
• Blood samples for PK analysis for all subjects.. Blood samples are to be taken prior to 
study drug dosing on Days 2, and  44. 
• 
Collection of AEs 
• 
Concomitant medications 
• 
Chemotherapy Cycles 1-4: Administration of F-627 20 mg fixed dose PFS or 
Neulasta® (performed once the study tests have been completed) as per the subject’s 
randomization arm. 
 
*Actual study day may vary due to each subject’s individual chemotherapy schedule.  
 
For Chemotherapy Cycle 1, Cycle Days 3-21*(corresponds to Study Days 3-21):  
 
• Body temperature 
• CBC with Differentials, local and central lab sample, blood smear sample 
• Blood samples for PK analysis, taken on Days 4 and 8. 
• Collection of AEs 
• Concomitant medications 
 
Final day of daily CBC draw is dependent on the individual subject’s ANC levels; daily 
tests to occur until subject’s ANC ≥ 2.0 × 109/L post-nadir is attained and then three days 
later. Investigators may use local lab draws to determine ANC levels for local ANC 
monitoring. 
 
For Chemotherapy Cycles 2-4, Cycle Days 3-21*(corresponds to Study Days 24-84):  
 
• Body temperature 
• CBC with Differentials, central lab sample, blood smear sample 
• Blood samples for PK analysis; to be taken on Days 4 and 8 for chemotherapy cycle 3. 
• Collection of AEs 
• Concomitant medications 
 
* Final day of daily CBC is dependent on individual subject’s ANC levels; tests to occur 


 
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(every other day) until subject’s ANC ≥ 2.0 × 109/L post-nadir is attained and then three 
days later. If the ANC level of a subject is < 0.5 for two consecutive visits, the subject must 
return the following day and then daily for an ANC blood draw until the ANC level is > 
0.5. Investigators may use local lab draws to determine ANC levels for local ANC 
monitoring. 
 
End of Treatment Visit  (20 days after last dose; corresponds to Study Day 84): 
 
• Physical examination 
• Body temperature 
• Vital Signs (BP and heart rate) 
• CBC with Differentials 
• Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, Bicarbonate, 
Calcium, Phosphorus, Glucose, Bilirubin, ALT, AST, Alkaline Phosphatase, GGT, 
LDH) 
• Serum pregnancy test, as appropriate  
• Serum collection for GCSF/F-627 antibody test 
• Urinalysis  
• Abdominal Ultrasound 
• ECG-12 lead 
• Collection of adverse events 
• Concomitant medications  
 
For those patients who withdraw early or upon study completion, a 28 day follow up 
telephone visit following their last clinical visit will be performed. Patient general function 
and feelings, relapse information, including concomitant medications, physician or hospital 
visits, and AE/SAE follow up will be assessed. 
 
6 Month Follow Up Visit  (6 months after last dose, +/- 5 days): 
 
• Physical examination 
• Vital Signs (BP and heart rate) 
• Serum collection for GCSF/F-627 antibody test 
• Disease progression/survival  
• G-CSF usage 
This visit will conclude the subject’s participation in the clinical trial. 




 
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18.3 Central Lab Locations 
Central Lab locations can be found in the study Lab Manual. There will be regional labs for 
North/South America, Eastern and Western Europe, and Asia. Study samples should be prepared 
and shipped per the lab manual instructions.   


 
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18.4 Definition of Abbreviations and Definitions of Terms 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil counts 
AST  
Aspartate aminotransferase 
AUC 
Area under the plasma concentration vs. time curve 
BUN 
Blood Urea Nitrogen 
Cmax  
Concentration Maximum 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CHO 
Chinese Hamster Ovary 
CL/F 
Oral Clearance 
eCRF 
Electronic Case Report Form 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EIU 
Exposure in Utero 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GMP 
Good Manufacturing Practices 
HIV 
Human Immunodeficiency Virus 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web-based Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRSD 
Maximum Recommended Starting Dose 
NCI 
National Cancer Institute 
NOAEL 
No Observed Adverse Effect Level 
PFS 
Prefilled syringe 
PK 
Pharmacokinetics 
PP 
Per Protocol 
rhG-CSF 
Recombinant human granulocyte colony stimulating factor 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 


 
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SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Maximum concentration (of a drug in bloodstream) 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Trial Sponsor: 
Generon (Shanghai) Corporation Ltd. 
Protocol Number: 
GC-627-05 
IND Number: 
 
Investigational Drug: 
F-627 
Indication: 
F-627 is indicated to decrease the incidence of infection, as manifested 
by febrile neutropenia, in patients with non-myeloid malignancies 
receiving myelosuppressive anti-cancer therapy associated with a 
clinically significant incidence of febrile neutropenia. 
Dosage Form/Strength: F-627, 20 mg fixed dose 
Neulasta® 6 mg fixed dose 
 
Protocol Title:  A Phase III Randomized, Multi-Centre, Open-Label, Fixed Dose, Neulasta® 
Active-Controlled Clinical Trial of F-627 in Women with Breast Cancer Receiving Myelotoxic 
Chemotherapy 
 
Last Revision Date: 
03 April 2017 
Version: 
1.0  
Final Sign-off Date: 
 
Archive Date: 
 
 
CONFIDENTIAL 
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
APPROVAL SIGNATURES 
 
Author: 
Shay Bagher, M.Sc. 
Biostatistician 
Everest Clinical Research 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
Peer Review Biostatistician: 
Francis Tang, M.Sc. 
Senior Manager 
Everest Clinical Research 
 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
Approved By: 
 
Dean Rutty, M.Sc. 
Executive Director, Biometrics 
Everest Clinical Research 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
Approved by: 
Kaiyang (Tom) Tang, MD, MBA 
Chief Medical Officer, Clinical and 
Regulatory Affairs 
Generon (Shanghai) Corporation 
 
 
 
  
 
 
 
 
Signature 
 
Date 
 
 
 
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4 Apr 2017


 
Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL 
Revision 
Date** 
Section(s)M
odified 
Brief Description of Revision(s) or 
Reason(s) for Revision 
Modifications Reviewed and 
Approved by* 
Sponsor, Everest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   Provide person’s initial and last name. 
** Update the Last Revision Dates on the cover page and the document header. 
 
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
TABLE OF CONTENTS 
APPROVAL SIGNATURES ........................................................................................................................ 2 
GLOSSARY OF ABBREVIATIONS .......................................................................................................... 6 
1. 
INTRODUCTION ................................................................................................................................ 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................ 8 
2.1 
Primary Efficacy Objective ........................................................................................................ 8 
2.2 
Primary Efficacy Endpoint ......................................................................................................... 8 
2.3 
Secondary Efficacy Endpoints .................................................................................................... 8 
2.4 
Additional Endpoints .................................................................................................................. 8 
2.5 
Safety Objective.......................................................................................................................... 9 
2.6 
...................................................................................................... 9 
2.7 
 ............................................................................................................... 9 
3. 
STUDY DESIGN .................................................................................................................................. 9 
3.1 
Study Design ............................................................................................................................... 9 
3.2 
Schedule of Assessments .......................................................................................................... 11 
3.3 
Randomization .......................................................................................................................... 12 
3.4 
Hypothesis Testing ................................................................................................................... 12 
3.5 
Interim Analysis ....................................................................................................................... 13 
3.6 
Sample Size .............................................................................................................................. 13 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE .................................................................. 13 
5. 
ANALYSIS POPULATIONS ............................................................................................................. 13 
5.1 
Intent-to-Treatment (ITT) Population ....................................................................................... 13 
5.2 
Per Protocol (PP) Population .................................................................................................... 13 
5.3 
Safety Population ...................................................................................................................... 14 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES ................................................................. 14 
6.1 
Demographic and Baseline Characteristics .............................................................................. 14 
6.1.1 
Demographics and Baseline Characteristics .............................................................. 14 
6.1.2 
Medical History, Surgery and Procedures History, Prior Cancer Systemic 
Therapy and Radiotherapy ......................................................................................... 14 
6.1.3 
Physical Examination ................................................................................................. 15 
6.1.4 
Prior and Concomitant Medication ............................................................................ 15 
6.1.5 
Myelotoxic Chemotherapy Administration ................................................................ 16 
6.1.6 
Steroid Administration ............................................................................................... 16 
6.2 
Efficacy ..................................................................................................................................... 16 
6.2.1 
Study Day and Relative Study Day ............................................................................ 16 
6.2.2 
Primary Efficacy Variables ........................................................................................ 16 
6.2.3 
Secondary Efficacy Variables .................................................................................... 17 
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
6.2.4 
Additional Variables................................................................................................... 18 
6.2.5 
 ................................................................... 19 
6.3 
 ....................................................................................................... 19 
6.4 
Safety ........................................................................................................................................ 19 
6.4.1 
Safety Baseline and Study Day .................................................................................. 20 
6.4.2 
Extent of Exposure to Study Medication.................................................................... 20 
6.4.3 
Adverse Events ........................................................................................................... 20 
6.4.4 
Laboratory Data .......................................................................................................... 22 
6.4.5 
Vital Signs .................................................................................................................. 22 
6.4.6 
Other Safety Assessments .......................................................................................... 23 
7. 
STATISTICAL ANALYSIS ............................................................................................................... 23 
7.1 
General Data Handling Rules and Definitions ......................................................................... 23 
7.1.1 
Data Exclusion and Missing Data Imputation ............................................................ 23 
7.2 
Subject Disposition ................................................................................................................... 24 
7.3 
Demographic and Baseline Characteristics .............................................................................. 24 
7.4 
Efficacy Analyses ..................................................................................................................... 25 
7.4.1 
Primary Efficacy ........................................................................................................ 25 
7.4.2 
Secondary Efficacy..................................................................................................... 25 
7.4.3 
Additional Endpoints .................................................................................................. 26 
7.5 
 ........................................................................................................ 27 
7.6 
................................................................................................................ 27 
7.7 
Safety Analyses ........................................................................................................................ 27 
7.7.1 
Extent of Exposure to Study Medication.................................................................... 27 
7.7.2 
Adverse Events ........................................................................................................... 27 
7.7.2.1 
Incidence of Adverse Events ..................................................................... 28 
7.7.3 
Laboratory Data .......................................................................................................... 28 
7.7.4 
Vital Signs .................................................................................................................. 28 
7.7.5 
Other Safety Assessments .......................................................................................... 29 
8. 
6-MONTH LONG-TERM FOLLOW-UP ANALYSES .................................................................... 29 
9. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................. 29 
10. STATISTICAL SOFTWARE ............................................................................................................. 29 
11. REFERENCES .................................................................................................................................... 29 
APPENDIX 1 
  DATA HANDLING RULES ................................................................................... 30 
APPENDIX 2 
  SAS CODE FOR STATISTICAL ANALYSES ...................................................... 30 
APPENDIX 3 
  MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) .................................... 30 
 
 
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
ANC 
Absolute neutrophil counts 
Cmax  
Concentration Maximum  
CBC 
Complete Blood Count 
CI 
Confidence interval 
CNS  
Central nervous system 
eCRF 
Electronic Case Report Form 
CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EU 
European Union  
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-Treat 
i.v. (IV) 
Intravenous 
IWRS 
Interactive Web-based Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
PFS 
Prefilled syringe  
PK  
Pharmacokinetics  
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
Abbreviation 
Term 
SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
WBC 
White Blood Cell 
 
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and analysis 
of data collected within the scope of Generon (Shanghai) Corporation Ltd. protocol GC-627-05, Protocol 
Version 1.0 dated February 16, 2017. The purpose of this plan is to provide general guidelines from 
which the analysis will proceed. Nevertheless, deviations from these guidelines must be substantiated by a 
sound statistical rationale. 
The SAP should be read in conjunction with the study protocol and the Case Report Forms (CRFs). This 
version of the SAP has been developed using the final version of the protocol mentioned above and the 
study CRFs.  
This is an open label; Phase III randomized study in women with stage I-III breast cancer to evaluate the 
efficacy of F-627 given as a single fixed dose (20 mg) pre-filled syringe as compared to Neulasta® 
standard dosing (6 mg) in the first chemotherapy cycle. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Efficacy Objective 
The primary objective of this study is to evaluate the efficacy of F-627 given as a single fixed dose 
(20 mg) pre-filled syringe (PFS) as compared to Neulasta® standard dosing (6 mg) in the first 
chemotherapy cycle.  
2.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the duration of grade 4 (severe) neutropenia, defined as the 
number of days in which the subject has had an ANC <0.5 × 109/L during cycle 1 of their chemotherapy 
treatment. 
2.3 
Secondary Efficacy Endpoints 
For all secondary and additional analyses, the F-627 group will each be compared to the Neulasta group. 
The secondary efficacy endpoints of this study are as follows: 
• 
The incidence rates of febrile neutropenia for each chemotherapy cycle and over all cycles. Febrile 
neutropenia is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of >38.0°C 
(100.4°F) sustained for >1 hour and ANC <0.5 x 109/L on the same day.  
• 
The time in days to ANC recovery post nadir for each chemotherapy cycle; recovery defined as an 
ANC ≥2.0 × 109/L after the expected ANC nadir. 
• 
The incidence rates of grade 4 neutropenia for each chemotherapy cycle. 
• 
The incidence and duration of use of intravenous (IV) antibiotics for each chemotherapy cycle and 
hospitalization for febrile neutropenia for each chemotherapy cycle.  
2.4 
Additional Endpoints 
• 
The duration in days of grade 4 (severe) neutropenia (ANC <0.5 x 109/L) for chemotherapy cycles 2, 
3, and 4. 
• 
The incidence rate of infections reported as AEs for each chemotherapy cycle. 
• 
The depth of the ANC nadir for each chemotherapy cycle. 
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
ANC level is ≥2.0 × 109/L, post-nadir. Once a subject’s ANC is ≥2.0 × 109/L post-nadir, the subject will 
return three days later for the last cycle 1 ANC measurement. Local blood samples maybe drawn to 
monitor subject ANC levels for neutropenia, however, local lab results of ANC will not be used in any 
study analysis. 
ANC Assessment for Chemotherapy Cycles 2, 3, 4: 
For chemotherapy cycles 2, 3, 4, subjects are required to return to the clinic every other day after study 
drug administration for blood draws to track ANC behavior post chemotherapy until ANC levels reach 
≥2.0 × 109/L, post-nadir. Once the subject’s ANC is ≥2.0 × 109/L post-nadir, the subject will return to the 
clinic three days later for the last ANC measurement for that chemotherapy cycle. Local blood samples 
maybe drawn to monitor subject ANC levels for neutropenia, however local lab results of ANC will not 
be used in any study analysis. 
 
 
 
 
Figure 1 Schematic Diagram and Trial Design 
 
Breast cancer Patients (TC) 
Day 1, Cycle 1  
Chemotherapy  
Randomization to Arm 1 or 2 
Arm 1: Day2, Cycle 1 
F-627 20 mg SC 
N=200 
Arm 2: Day2, Cycle 1 
Neulasta® 6mg SC 
N=200 
Day2, Cycle 2-4 
Chemotherapy 
F-627 20 mg SC 
Day2, Cycle 2-4 
Chemotherapy 
Neulasta® 6mg SC 
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
3.3 
Randomization 
Eligible subjects in this study will be randomized to receive F-627 20 mg/dose or 6 mg/dose Neulasta® in 
a 1:1 ratio. An interactive web-based response system (IWRS) with a 24-hour live support Helpdesk will 
be used for randomization in the study.  
Although the study is considered “open-label” due to differences in study drug presentations, the primary 
endpoint is based on a laboratory measurement (ANC) that is not subject to bias. As a result, study drug 
injections will be administered by qualified study personnel and investigators should remain blinded and 
perform all assessments without knowledge of treatment assignment. 
Subjects will be randomized and stratified by country/region. All arms will be utilized concurrently. 
3.4 
Hypothesis Testing 
Primary Efficacy Analysis 
For the primary efficacy analysis, non-inferiority test will be used to explore the duration of grade 4 
(severe) neutropenia between F-627 vs. Neulasta in cycle 1 within 12 days of chemotherapy treatment. 
The following null and alternative hypotheses for comparisons between F-627 vs. Neulasta will be tested: 
H0: µF-627 - µNeulasta ≥ 0.6 days vs. Ha:  µF-627 - µNeulasta < 0.6 days   
Non-inferiority of F-627 to Neulasta is observed when the upper limit of the two-sided 95% confidence 
interval (CI) for the difference in mean duration of grade 4 neutropenia is < 0.6 days. This is equivalent to 
using a one-sided significance level of 0.025 for the comparison. 
If the null hypothesis is rejected and F-627 is deemed non-inferior to Neulasta, then the two sided CI will 
be assessed to determine superiority.  Superiority will be claimed if the upper and lower bound of the CI 
is < 0. 
 
Secondary Efficacy Analysis 
If the primary analysis infers F-627 non-inferior to Neulasta, then the secondary endpoints will be tested 
using a fallback method in order to retain the type I error rate1, 2, 3, 4, 5, 6. Similar to fixed sequence 
procedure, the fallback method tests hierarchically ordered hypotheses in sequence but splits the level of 
α between the hypotheses. Unlike fixed sequence procedure, the fallback procedure tests all hypotheses in 
the pre-specified sequence even if the initial hypotheses are not rejected. As a result, the fallback method 
for ordered hypotheses provides the opportunity to test an endpoint later in the sequence and gains 
additional power by allocating a higher α level to a hypothesis if the hypothesis earlier in the sequence is 
rejected. 5,6 The sequence of secondary endpoints and their allocated α is listed below: 
1. The duration of intravenous (IV) antibiotics, α=0.0485 (total across all chemotherapy cycles). 
2. The duration of hospitalization for febrile neutropenia or any infection, α=0.001(total across all 
chemotherapy cycles). 
3. The incidence rates of febrile neutropenia, considering all chemotherapy cycles, α=0.0001. 
4. The time in days to ANC recovery post nadir for chemotherapy cycle 1, α=0.0001. 
5. The incidence rates of grade 4 neutropenia for chemotherapy cycle 1, α=0.0001. 
6. The incidence of use of intravenous (IV) antibiotics, considering all chemotherapy cycles, α=0.0001. 
7. The incidence of hospitalization for febrile neutropenia, considering all chemotherapy cycles, 
α=0.0001.  
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Statistical Analysis Plan 
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3.5 
Interim Analysis 
No interim analysis is planned for this study.   
3.6 
Sample Size 
The assumptions used to calculate the study sample size are based on the results from the GC-627-02 
Phase II study. For subjects dosed with TC chemotherapy, the difference in the duration of severe 
neutropenia for F-627 in this study as compared to Neulasta® was 0.3 and 0.1 days, for the 240 and 320 
μg/kg arms respectively, with an observed standard deviation of 0.28 days for Neulasta®, 0.86 and 0.48 
days for F-627 240 and 320 μg/kg arms respectively. Assuming a difference in the duration of severe 
neutropenia for F-627 as compared to Neulasta® of up to 0.3 days and a common standard deviation of 
0.86 days, with a non-inferiority margin of 0.6 days, a sample size of 174 per arm would be required to 
realize 90% power under these assumptions. Assuming a 10% drop-out rate, a total sample size of 386 
should be randomized across both treatment arms. 
4. DATA AND ANALYTICAL QUALITY ASSURANCE 
The overall quality assurance procedures for the study data, statistical programming and analyses are 
described in the Everest’s Standard Operating Procedures. Detailed statistical and programming quality 
control and quality assurance procedures are documented in the Statistical Analysis and Programming 
QC/QA Plan.  
The study endpoints and analytic approaches are both prospectively defined and documented in the 
protocol and in this SAP finalized prior to the database lock and data analysis. 
5. ANALYSIS POPULATIONS 
5.1 
Intent-to-Treatment (ITT) Population 
All randomized subjects will be included in the ITT Analysis Set. Following the ITT principle in the ICH 
E9 guidance, the data of all the participants in the ITT Analysis Set will be analyzed according to their 
randomized treatment. The ITT Analysis Set will be used for sensitivity analyses of the primary endpoint 
with respect to non-inferiority and will be the primary analysis population for all secondary efficacy 
endpoints. 
5.2 
Per Protocol (PP) Population 
All subjects from the ITT Analysis Set who received study treatment, who are eligible and compliant and 
without major protocol deviations during the first cycle of treatment will be included in the PP Analysis 
Set. Major protocol deviations and subjects (or data) excluded from the PP Analysis Set will be defined 
by the Sponsor in a blinded manner prior to database lock. The PP Analysis Set will be used as the 
primary Analysis Set in the non-inferiority efficacy analysis and for sensitivity analysis of all secondary 
endpoints. Major protocol deviations include, but are not limited to, receiving incorrect treatment, or non-
compliance to ANC collection in the first 12 days of cycle 1 that may affect the primary endpoint.  
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
5.3 
Safety Population 
All enrolled subjects receiving F-627 or Neulasta treatment will be included in the Safety Analysis Set, 
which will be used for all safety analyses. The data in the Safety Analysis Set will be analyzed according 
to the treatment received. 
6. SPECIFICATION OF ENDPOINTS AND VARIABLES 
Several analytic variables must be derived from the data as it was collected. This section describes the 
variables collected, as well as how they will be modified for inclusion in the analyses. 
6.1 
Demographic and Baseline Characteristics 
6.1.1 
Demographics and Baseline Characteristics 
Demographic parameters collected include: sex, race/ethnicity, country/region, reproductive status, 
weight (kg) and height (cm).  
Age, body mass index (BMI), body surface area (BSA) and days since diagnosis will be computed as: 
Description 
Data Handling Rule 
Age (years) 
Age = integer((date of informed consent-date of birth)/365.25)   
BMI 
BMI = Weight (kg) / [Height (cm)/100]2 
BSA 
BSA =( [Height (cm) x Weight (kg) ]/ 3600 )1/2 
Days since diagnosis 
Days since diagnosis = Date of randomization – Date of 
diagnosis 
 
Baseline characteristics, including Screening ECOG performance score (0 to 2) and stage of cancer (I to 
III) will also be summarized. 
6.1.2 
Medical History, Surgery and Procedures History, Prior Cancer Systemic 
Therapy and Radiotherapy 
Medical history, surgery and procedure history and prior cancer systemic therapy and radiotherapy will be 
collected at the Screening visit. 
General medical history will be collected by category (assigned by investigator on the eCRF), and will 
include description of the condition/finding, onset and end date, and if the condition is still present 
(yes/no). 
Surgery and procedure history will be categorized by indication (breast cancer, other cancer or general). 
Description and date of surgery/procedure will be collected on the eCRF. 
Prior cancer systemic therapy will be categorized by therapy code:  
• 
Chemo/anthracycline 
• 
Chemo/non-anthracycline 
• 
Hormonal 
• 
Biologic 
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Statistical Analysis Plan 
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• 
Myeloablative therapy 
• 
Bone marrow or stem cell transplant 
• 
Other 
Agent name, reason for stopping and first/last dose dates will be recorded on the eCRF. 
Prior cancer radiotherapy will be categorized by radiation site: 
• 
Right breast 
• 
Left breast 
• 
Bone 
• 
Liver 
• 
Lung 
• 
Lymph nodes 
• 
Abdomen 
• 
Mediastinum 
• 
Central nervous system (CNS) 
• 
Pelvis 
• 
Skin/Soft tissue 
• 
Other 
Radiation site description and last dose date will be collected on the eCRF. 
6.1.3 
Physical Examination 
A physical examination will take place at screening and at each clinical visit as presented in the schedule 
of assessment (Table 1). Any change from baseline will be evaluated and assessed by the Investigator. An 
abbreviated physical exam may be completed at any visit as deemed appropriate by medical staff. Results 
of such abbreviated physical exams will be collected on the eCRFs. 
6.1.4 
Prior and Concomitant Medication 
Prior and concomitant medications will be recorded at screening and during the study. Prior medication is 
defined as any medication taken before the first dose of chemotherapy. Concomitant medication is 
defined as any medication taken during the study between the date of the first dose of chemotherapy and 
the date of subject discharge from the study three weeks after last dose of study drug or at the time of 
early termination. Any medication that started after the subject discharge from the study three weeks after 
last dose of study drug or at the time of early termination will not be considered a concomitant 
medication. 
Any medication which cannot be identified as prior or concomitant will be considered as being in both of 
the categories that are possible from the available information. 
All prescription and over-the-counter (OTC) medications, including herbal supplements, taken by the 
subject within 3 months prior to the Screening visit and throughout the study will be recorded on the Prior 
and Concomitant Medications form.  
Any additions, deletions, or changes in the dose of these medications while on study should be recorded. 
Any current ongoing medications, including OTC drugs and herbal supplements, will be allowed 
provided they are not prohibited by the protocol and are approved by the Investigator. 
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Statistical Analysis Plan 
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Medications will be coded using latest version of the World Health Organization Drug Dictionary (WHO-
DD) available. 
6.1.5 
 Myelotoxic Chemotherapy Administration 
For each of the four cycles, the following chemotherapy administration details will be collected on Cycle 
Day 1, for each of the two agents (Taxotere and Cyclophosphamide): 
• 
Infusion date and start/end time  
• 
Dose level: 
• 
Taxotere: 75 mg/m²  
• 
Cyclophosphamide: 600 mg/m²  
• 
Actual dose given (mg) 
6.1.6 
Steroid Administration 
Steroids (Dexamethasone at a dose level of no more than 8 mg BID) administered on the day before, the 
day of and the day after chemotherapy will be collected on the eCRF at the beginning of each cycle.   
6.2 
Efficacy 
The per-protocol (PP) population and intent-to-treat (ITT) population will be used for the efficacy 
analyses. Efficacy analysis of non-inferiority will be primarily based on the PP analysis population and 
efficacy analysis of superiority will be primarily based on the ITT population. The ITT analysis 
population will also be used for sensitivity analysis for the non-inferiority analysis. 
There will be no imputation of the missing primary endpoint data in the PP analysis.  Handling of missing 
values is covered in section 7.1.1. 
6.2.1 
Study Day and Relative Study Day 
The date of the first dose of chemotherapy in Cycle 1 represents Study Day 1. 
Study day will be computed from cycle 1, day 1 as:   
Study day = (date of interest) – (date of Study Day 1) + 1 
For each cycle, the date of the first dose of chemotherapy represents Relative Study Day 1. 
Relative study day will be based on each cycle as: 
Relative study day = (date of interest) – (date of Relative Study Day 1) + 1 
6.2.2 
Primary Efficacy Variables 
The duration of grade 4 (severe) neutropenia is defined as the number of days in which the subject has 
had an ANC < 0.5 × 109/L during cycle 1. 
Duration = (Date of last ANC < 0.5 × 109/L within cycle) – (Date of first ANC <0.5 × 109/L within cycle) + 1 
If subject does not experience neutropenia during the first 12 days of cycle 1, Duration = 0 days. 
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Statistical Analysis Plan 
Protocol Number: GC-627-05 
 
 
6.2.3 
Secondary Efficacy Variables 
For all secondary and additional analyses, the F-627 group will be compared to the Neulasta® group. 
The secondary endpoints are: 
• 
The incidence rates of febrile neutropenia for each chemotherapy cycle and over all cycles. 
Febrile neutropenia is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of 
>38.0°C (100.4°F) sustained for >1 hour and ANC <0.5 x 109/L. Investigators are to report 
occurrences of febrile neutropenia as an AE. 
Incident rate (%) = 100% × (Number of subjects with at least one incidence of febrile neutropenia 
/Total number of subjects with post-baseline ANC value) 
Febrile neutropenia will be based on AE reporting and MedDRA coding. If a subject has more 
than one incidence of febrile neutropenia, it will be counted only once when calculating the 
incidence of febrile neutropenia over all cycles. 
To determine the cycle of a febrile neutropenia event: 
Cycle of event = i, if Day 1 of Cycle i ≤ Start Date of Event < Day 1 of Cycle (i+1), when i is not 
the last cycle observed for the subject.  
Cycle of event = i, if Day 1 of Cycle i ≤ Start Date of Event ≤ Min(End of Study, Last Contact 
Date, 3 Weeks after Last Cycle), when i is the last cycle observed for the subject. 
 
• 
The time in days to ANC recovery post nadir for each chemotherapy cycle; recovery defined as 
an ANC ≥2.0 × 109/L after the expected ANC nadir. 
Nadir is the lowest observed ANC value in the first 12 days of that cycle. In case there are more 
than one lowest ANC values within 12 days chemotherapy treatment, the first point will be used 
as nadir. 
If at nadir point, ANC < 2.0 × 109/L, then: 
ANC Recovery = (Date when ANC ≥ 2.0 × 109/L) – (Date of nadir in this cycle) + 1 
If ANC ≥ 2.0 × 109/L during the first 12 days of cycle, then ANC Recovery = 0 days. 
 
• 
The incidence rates of grade 4 neutropenia for each chemotherapy cycle and over all cycles.  
Incident rate (%) = 100% × (Number of subjects with at least one incidence of grade 4 neutropenia / 
Total number of subjects with post-baseline ANC value) 
Grade 4 neutropenia will be based on ANC values. If a subject has more than one incidence of 
febrile neutropenia, it will be counted only once. 
To determine the cycle of a febrile neutropenia event: 
Cycle of event = i, if Day 1 of Cycle i ≤ Start Date of Event < Day 1 of Cycle (i+1), when i is not 
the last cycle observed for the subject.  
 
Cycle of event = i, if Day 1 of Cycle i ≤ Start Date of Event ≤ Min(End of Study, Last 
Contact Date, 3 Weeks after Last Cycle), when i is the last cycle observed for the subject. 
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Statistical Analysis Plan 
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• 
The incidence and duration of use of intravenous (IV) antibiotics for each chemotherapy cycle 
and over all cycles. 
Incident rate (%) = 100% × (Number of subjects with at least one incidence of intravenous (IV) 
antibiotics / Total number of subjects with post-baseline ANC value) 
Intravenous (IV) antibiotics are based on concomitant medication reporting and WHO Drug 
coding. If a subject has more than one incidence, it will be counted only once. 
To determine the cycle of an intravenous (IV) antibiotics event: 
Cycle of event = i, if Day 1 of Cycle i ≤ Start Date of Event < Day 1 of Cycle (i+1), when i is not 
the last cycle observed for the subject.  
Cycle of event = i, if Day 1 of Cycle i ≤ Start Date of Event ≤ Min(End of Study, Last Contact 
Date, 3 Weeks after Last Cycle), when i is the last cycle observed for the subject. 
The duration of intravenous (IV) antibiotics is defined as the cumulative number of days in which 
the subject has had intravenous (IV) antibiotics over the study period. 
Duration = Sum of [(Date of last Intravenous (IV) Antibiotics within a cycle) – (Date of first 
Intravenous (IV) Antibiotics within a cycle) + 1] for all cycles with antibiotic use.  
• 
The incidence and duration of hospitalization for febrile neutropenia for each chemotherapy cycle 
and over all cycles. 
Incident rate (%) = 100% × (Number of subjects with at least one incidence of hospitalization for 
febrile neutropenia / Total number of subjects with post-baseline ANC value) 
Hospitalization for febrile neutropenia are based on SAE reporting where MedDRA coding is 
used to identify febrile neutropenia. If a subject has more than one incidence, it will be counted 
only once. 
To determine the cycle of hospitalization for febrile neutropenia event: 
Cycle of event = i, if Day 1 of Cycle i ≤ Start Date of Event < Day 1 of Cycle (i+1), when i is not 
the last cycle observed for the subject.  
Cycle of event = i, if Day 1 of Cycle i ≤ Start Date of Event ≤ Min(End of Study, Last Contact 
Date, 3 Weeks after Last Cycle), when i is the last cycle observed for the subject. 
The duration of hospitalization for febrile neutropenia is defined as the cumulative number of 
days in which the subject was hospitalized for febrile neutropenia. 
Duration = Sum of (Date of last hospitalized for febrile neutropenia) – (Date of first hospitalized 
for febrile neutropenia within a cycle) + 1] for all cycles with antibiotic use.  
6.2.4 
Additional Variables 
• 
The duration in days of grade 4 (severe) neutropenia for chemotherapy cycles 2, 3, and 4. 
The duration of grade 4 (severe) neutropenia is defined as the number of days in which the 
subject has had an ANC < 0.5 × 109/L during cycle 2, 3 and 4. 
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Statistical Analysis Plan 
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Standard safety parameters include hematology, blood chemistry and urinalysis parameters, vital signs, 
physical examination, and symptom/toxicity assessment. The National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03 will be used to grade potential AEs. 
Local blood samples maybe used to determine the status of a subject’s ANC level for local safety 
monitoring and evaluation. 
6.4.1 
Safety Baseline and Study Day  
The baseline of safety measures are the last measure before chemotherapy of Cycle 1. 
Study day will be computed from cycle 1, day 1 as:   
Study day = (Date of interest) – (Date of Cycle 1 Day 1) + 1 
6.4.2 
Extent of Exposure to Study Medication 
Extent of exposure to study drug will be assessed using the following variables: 
Description 
Data Handling Rule 
Treatment duration 
Treatment duration (weeks) = (Date of last F-627/Neulasta dose – 
Date of first F-627/Neulasta dose + 1) / 7 
Total dose taken 
F-627: Total dose taken (mg) = ∑i=1 to 4 Total volume injected 
(fixed 20 mg/cycle) 
Neulasta: Total dose taken (mg) = ∑i=1 to 4 Total volume injected 
(fixed 6 mg/cycle) 
Total dose expected 
F-627:4 x 20 mg=80 mg 
Neulasta: 4 x 6 mg=24 mg 
Study drug compliance 
Study drug comp (%) = (Total dose taken / Total dose expected) 
× 100%. 
 
Study drug compliance will be treated as a continuous variable and categorized as follows: 
• 
>110% 
• 
>100-110% 
• 
>90 - 100% 
• 
>80 - 90%  
• 
>70 - 80% 
• 
>60 - 70% 
• 
>50 - 60% 
• 
≤50% 
6.4.3 
Adverse Events 
Adverse events (AEs) will be collected and coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Analysis of adverse events will be carried out on the safety population. 
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Statistical Analysis Plan 
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A treatment-emergent adverse event (TEAE) is any adverse event that begins on or after first 
chemotherapy treatment or is a worsening of a pre-existing medical condition. Incidence of TEAE will be 
presented by treatment group. SAEs will be collected from the time of randomization until 30 days after 
completion of the trial or 30 days after premature withdrawal of a subject from the trial.  
The severity of each AE will be classified using the NCI-CTCAE toxicity scale as follows: 
• 
Grade 1 = Mild 
• 
Grade 2 = Moderate 
• 
Grade 3 = Severe and undesirable 
• 
Grade 4 = Life-threatening or disabling 
• 
Grade 5 = Death 
The relationship of each AE will be assessed by the investigator in one of the following categories: 
• 
Unrelated 
• 
Unlikely 
• 
Possible 
• 
Probable 
• 
Definite 
An AE will be considered “related” to study drug if the relationship is “unlikely”, “possible”, “probable” 
or “definite”. 
Serious adverse events (SAE) are defined as any adverse events occurring at any dose that suggests a 
significant hazard, contraindication, side effect, or precaution. SAEs will be collected from the time of 
randomization until 30 days after completion of the trial or 30 days after premature withdrawal of a 
subject from the trial. 
If the death of a subject is reported at any point during the study, the date of death, autopsy performed 
(yes/no), and any clarifying information should be collected. The event causing death will be reported as a 
SAE. 
Adverse Events Counting Rules: 
1. In the analyses, a subject having the same event (AE preferred term) more than once during the study 
will be counted only once for that event type.  
2. A subject with more than one different adverse event in a particular system organ class (SOC) will be 
counted only once in the total of subjects experiencing adverse events in that particular SOC. 
3. If an event changes in intensity or in seriousness during the study, it will be counted only once with 
the worst grade and seriousness respectively. 
4. If the causal relationship to the study drug is assessed differently, it will be counted only once by 
considering the “Worst” documented degree of relationship. 
Missing values will be treated as missing except for relationship, grade and seriousness of an AE, at 
which occurrence a “worst case” approach will be taken. Thus, if relationship is missing the AE will be 
regarded as related to the study drug, if the grade is missing the grade of the AE will be regarded as 
severe (Grade 3), if seriousness is missing the AE will be regarded as an SAE. 
Events with Irregular Start Dates: All treatment-emergent adverse events will be included in the 
tabulations regardless the completeness of the onset dates. Partial dates may be imputed when 
appropriate, as discussed below. 
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Statistical Analysis Plan 
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If a partial date is reported for the start of an adverse event, a complete date will be estimated by the 
following algorithm: 
1. Only the year is reported: If the subject started receiving study medication in the prior year, then 
January 1 will be used as the starting date of the event. If the subject started receiving study 
medication in the year reported, then the date of the first dose of study medication will be used as the 
start of the event.  
2. The month and year are reported: If the subject started receiving study medication prior to the month 
and year reported, then the first day of the month will be used as the starting date of the event. If the 
subject started receiving medication during the month and year reported, then the date of the first dose 
of study medication will be used as the start of the event.  
If a partial date is reported for the end of an adverse event and the adverse event is not continuing, a 
complete date will be estimated by the following algorithm:  
1. Only the year is reported: If the subject started receiving study medication in the prior year, then the 
date of final study contact with the subject will be used as the end of the adverse event. If the subject 
started receiving study medication in the year reported, the earlier of December 31 or the date of final 
study contact with the subject will be used as the end of the adverse event.  
2. The month and year are reported: The earlier of the last day of the month or the date of final contact 
with the subject will be used as the end of the adverse event.  
Before the database lock, uncoded events will be assigned the string “UNCODED” as the body system, 
and the verbatim term will be used as the preferred term, so they can be included in the summary tables. 
In the final dataset, all the adverse events should have been coded.  
6.4.4 
Laboratory Data 
Only Central lab results will be used for statistical analysis to ensure consistent measurements throughout 
the duration of the clinical trial.  
Conversion to the International System of Units 
All laboratory data will be stored in the database with the units in which they are originally reported. 
Laboratory data in summary tables and subject data listings will be presented in the International System 
of Units (SI units). Laboratory data not reported in SI units will be converted to SI units before further 
processing or data analysis. 
Hematology and blood chemistry data will be graded according to NCI-CTCAE severity grade.  
Baseline laboratory parameters (blood chemistry, hematology, and urinalysis) are defined as the subject’s 
last assessment prior to Cycle 1 Day 1of the initiation of chemotherapy.  
Change in laboratory parameters post baseline can be computed as: 
Change from baseline = Current Value – Baseline Value 
Missing laboratory values will not be imputed for the safety analysis. In case of repeated measurements at 
a given visit, the latest value will be used for analysis.   
6.4.5 
Vital Signs 
Vital signs are collected at Screening, each cycle’s Relative Day 1 and Relative Day 2, and at end of 
study, and include the following parameters: 
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Statistical Analysis Plan 
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• 
Height (cm) (Screening only) 
• 
Weight (kg) 
• 
Heart rate (beats per minute [BPM]) 
• 
Diastolic and systolic blood pressure (mmHg) 
Baseline and change from baseline are defined similarly as in Section 6.4.4.  
6.4.6 
Other Safety Assessments 
Other safety assessments include: 
• 
Serum pregnancy test  
• 
Chest X-Ray  
• 
Abdominal ultrasound  
• 
Tuberculosis (TB) screening 
• 
ECG 
• 
Physical examination 
Any clinically significant abnormalities from physical examination, ECG test, abdominal ultrasound or 
chest x-ray will be reported as medical history if observed at Screening, or as an AE if observed after 
randomization. 
7. STATISTICAL ANALYSIS 
7.1 
General Data Handling Rules and Definitions 
All subjects randomized will be accounted for in the statistical analysis and presentation of the trial 
results.  
All data collected on case report forms will be provided in listings, except data collected only for 
confirmation of study entry criteria and for study administrative purposes. If any randomized subject is 
found to not have valid documented informed consent, that subject’s data will be excluded from the 
report.  
Except where specified, all continuous variables will be summarized with descriptive statistics (the 
number of non-missing values, mean, standard deviation, median, minimum and maximum) and all 
categorical variables will be summarized with frequency counts and percentages, by treatment group. 
Missing data will be maintained as missing unless specified otherwise.  For variables where missing data 
is imputed, the analysis dataset will contain one variable with the imputed value and the original variable 
with missing maintained as missing. 
7.1.1 
Data Exclusion and Missing Data Imputation 
Missing data will be maintained as missing for PP analysis. Critical efficacy data and major protocol 
deviations will be reviewed in a blinded manner prior to database lock to determine the subjects to be 
excluded from the PP Analysis. The meeting minutes with detailed reasons for subject exclusion will be 
reviewed and approved by the sponsor before database lock and filed in the clinical study report (CSR) 
Appendices.     
In the ITT population, missing ANC data between day 1 and day 12 of each cycle for all ANC related 
endpoints will be imputed using two approaches.  
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Statistical Analysis Plan 
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• 
If ≤ 2 consecutive ANC readings are missed, missing ANC values will be imputed using the 
worst of the two adjacent values of the missing result for that cycle. 
• 
Otherwise, if > 2 consecutive ANC reading are missed, the average of the ANC measured on that 
day of that cycle for the assigned treatment arm will be used to impute each specific missing 
value. 
In analyzing duration of IV antibiotics and hospitalizations, missing data will be maintained as missing 
unless specified otherwise. Every effort will be made to ensure there are no missing start or end dates for 
IV antibiotics or hospitalizations. In the unlikely event that the start date or end date of IV antibiotic use 
or hospitalization is missing, the duration will be imputed using the maximum duration within the  
treatment group randomized. The non-imputed data will be displayed in the subject listings.  
7.2 
Subject Disposition 
Disposition tables will be presented by treatment group and for all subjects.  
The number and percentage of subjects who failed the screening, were randomized into the study, and 
completed each of the four chemotherapy cycles will be tabulated. The number and percentage of subjects 
included and excluded from the defined analysis populations and reasons for study discontinuation will 
also be summarized for each treatment group. Other disposition information, reasons for screen failure 
and study discontinuation details will be provided in individual subject data listings.  
Major protocol deviations, such as significant non-compliance or other serious unforeseen violations 
deemed to invalidate the data collected for the purpose of the study will lead to exclusion of the data from 
the Per Protocol (PP) analysis population for efficacy analysis. In case of minor protocol violations, data 
will not be excluded from the efficacy analysis. The rating of protocol violations as “minor” or “major” 
will be decided on the basis of a blinded review of the data before declaration of “clean file” and lock of 
database. 
All major protocol deviations will be presented in subject data listings.  
7.3 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics variables will be summarized by treatment and all data will be 
provided in listings. 
Continuous baseline parameters (such as age, height, weight, BSA) will be summarized descriptively. For 
categorical baseline and demographic parameters (such as country, reproductive status, ethnicity, stage of 
cancer) frequencies of subjects will be provided. 
Number and percentage of subjects with medical history (any and by category) and systemic therapy (any 
or by therapy) will be summarized relative to the total number of subjects in the population analyzed. All 
data collected on the eCRF will be presented in listings. 
Prior and concomitant medications including those ongoing at baseline will be tabulated by ATC class 
and preferred term. Number and percentage of subjects with prior medications will be provided by 
treatment group and for all subjects combined. Other details, including medication verbatim and coding, 
will be presented in listings. A glossary of all medications will also be provided. 
Myelotoxic chemotherapy administration on cycle day 1 will be tabulated for each agent. The percentages 
of subjects administered each dose level of Taxotere and Cyclophosphamide (TC chemotherapy) will be 
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Statistical Analysis Plan 
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summarized relative to the safety analysis population for all subjects. Exact dose and timing will be 
provided in listings. 
Chemotherapy and steroid administration data during the study will be listed. 
7.4 
Efficacy Analyses 
All testing will be two-sided, with “statistical significance” defined as a corresponding p-value < 0.05, 
with the exception of the primary analysis and fallback hierarchical testing of the secondary endpoints 
whose “statistical significance” is defined in section 3.4. The fallback method of testing the secondary 
endpoints will be employed in order to retain the type 1 error rate if non-inferiority is observed in the 
primary analysis. 
The analyses of the secondary endpoints will be carried out in the following hierarchical order shown in 
section 3.4 to account for multiplicity in the testing of each. Each hierarchical testing sequence will 
permit the conservation of type 1 error within each of the two active treatment group comparisons. 
A significant P value from secondary endpoint 1 will be necessary to initiate secondary endpoint 2, and so 
on. Since a hierarchical procedure will be used, the type 1 error rate will be preserved for each of the 
comparisons between the two groups.  
7.4.1 
Primary Efficacy 
The primary objective of this study will be to evaluate the efficacy of F-627 given as a single fixed dose 
(20 mg) as compared to Neulasta® standard dosing (6 mg) in the first chemotherapy cycle. The primary 
endpoint will be the duration in days of grade 4 (severe) neutropenia (ANC < 0.5 x 109/L) observed in 
chemotherapy cycle 1. A non-inferiority analysis will be performed, with a margin of 0.6 days, to 
compare the F-627 arm to Neulasta® with respect to the duration of severe neutropenia.  
The duration of grade 4 neutropenia in cycle 1 will be summarized descriptively by treatment group and 
for all subjects in the PP analysis population as the number of days ANC <0.5x 109/L. 
Non-inferiority tests will be performed to compare mean duration of grade 4 neutropenia in cycle 1 
between F-627 vs Neulasta® for all subjects. The difference in mean duration of neutropenia between 
each of the F-627 and Neulasta® for cycle 1 will be calculated as: mean (F-627) – mean (Neulasta®). 
Non-inferiority tests will be performed to compare mean duration of grade 4 neutropenia in cycle 1 
between F-627 vs Neulasta® for all subjects. Two-sided 95% confidence intervals (CI) will be provided. 
Non-inferiority of F-627 to Neulasta® will be claimed if the upper limit of the two-sided 95% CI is less 
than 0.6 days. This is equivalent to using a one-sided significance level of 0.025. 
If found to be non-inferior to Neulasta®, superiority of F-627 to Neulasta® will be assessed in a similar 
manner: if the upper limit of the two-sided 95% CI is less than 0 day, the tested dose of F-627 will be 
considered superior to Neulasta®.   If superiority is observed for the PP analysis set, then the superiority 
analysis will be repeated for the ITT analysis set. 
7.4.2 
Secondary Efficacy 
A fallback testing method of the secondary endpoints will be employed in order to retain the type 1 error 
rate if the non-inferiority is observed in the primary analysis. The order of the hierarchical testing and the 
assigned α are detailed in Section 3.4. 
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Statistical Analysis Plan 
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Febrile neutropenia: 
The frequency and percentage of subjects with febrile neutropenia will be summarized for each cycle and 
over all cycles. The difference in percentage between the F-627 and Neulasta® groups will be tested by 
Fisher’s exact test. 
Time to ANC recovery: 
The difference in number of days of ANC recovery (ANC ≥2.0 × 109/L) from ANC nadir between F-627 
and Neulasta® in each cycle will also be compared with a 95% CI. 
For visual comparison of the effectiveness of the F-627 dose to Neulasta®, the logarithm of mean and 
median ANC over time (day) for each group will be plotted for cycle 1. Similar ANC profiles will be 
plotted for cycles 2, 3 and 4. 
Incidence rates of grade 4 (severe) neutropenia for all chemotherapy cycles: 
The frequency and percentage of grade 4 neutropenia for each chemotherapy cycle and over all cycles 
will be summarized. The incidence difference of grade 4 neutropenia between F-627 and Neulasta® will 
be tested by Fisher’s exact test for cycle 1. 
The incidence and duration of use of IV antibiotics and hospitalization for FN or infection: 
The durations of IV antibiotic use and hospitalization for FN or infection will be summarized for each 
cycle and over all cycles.  The differences in duration between F-627 and Neulasta groups will be tested 
using a t-test or, if the data are not normally distributed, a Wilcoxon rank-sum test. 
The frequency and percentage of subjects using IV antibiotics and the frequency and percentage of 
subjects hospitalized for FN or infection will be summarized for each cycle and over all cycles. The 
differences in percentage between the F-627 and Neulasta® groups will be tested by a chi-square test for 
each cycle and over all cycles; if the number of events observed is less than 5, this difference will be 
tested using Fisher’s exact test. 
7.4.3 
Additional Endpoints 
Duration of grade 4 (severe) neutropenia for cycles 2–4: 
The duration of grade 4 neutropenia within 12 days of chemotherapy treatment for cycles 2, 3, and 4 will 
be summarized. 
Incidence rate of infections: 
The number and percentage of subjects with infections will be summarized for each cycle and over all 
cycles. The difference in percentage between the F-627 and Neulasta® groups will be tested by a Chi-
Square test for each cycle and over all cycles. 
Depth of ANC nadir:  
The lowest ANC values within 12 days of chemotherapy treatment will be summarized for each cycle. A 
two-sided 95% CI of the ratio of ANC nadir between F-627 and Neulasta will be calculated by Fisher’s 
exact test for each cycle and over all cycles. 
Ratio to Neulasta = ANC nadir value of F-267 group/ANC nadir value of Neulasta group 
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Statistical Analysis Plan 
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7.7.2.1 
Incidence of Adverse Events 
TEAEs will be summarized by treatment group by system organ class (SOC) and preferred term (PT). 
The summary tables will display the total number and percentage of subjects reporting a specific TEAE, 
and the number of TEAE reported. TEAEs will be presented by system organ class (SOC) sorted 
alphabetically and preferred term (PT) sorted in decreasing frequency of occurrence. 
Summary tables will be prepared for: 
• 
Summary of TEAEs (including Febrile neutropenia and Injection site reaction) 
• 
All TEAEs 
• 
Serious TEAEs 
• 
Treatment-related TEAEs 
• 
TEAE leading to study drug discontinuation 
• 
TEAEs by NCI-CTCAE grade 
• 
Common TEAEs with > 5% incidence rate in any treatment group 
• 
TEAEs by relationship (unrelated/unlikely/possible/probable/definite) 
Supporting data listings will be provided by chemotherapy regimen and treatment group, including: 
• 
All adverse events (including any AEs reported in the study)  
• 
Serious adverse events  
• 
Adverse events leading to death 
• 
Adverse events for subjects who discontinued the study due to AE 
• 
Adverse events of special interest (Febrile Neutropenia) 
• 
Adverse events of special interest (Infections) 
• 
Glossaries of Preferred terms to verbatim by System Organ Class (SOC) 
Injection site reactions details will be summarized similarly by parameter and time point for each cycle 
and all cycles combined. 
7.7.3 
Laboratory Data 
For the analysis purpose, the study visit/time point will be recalculated using the dates of Relative Day 1 
collected from Myelotoxic Chemotherapy eCRF page for each cycle. 
Descriptive statistics will be presented for value at baseline and change from baseline at cycles 1-4 
Relative Day 2 and end-of-study for each continuous laboratory parameter. Number and percentage of 
subjects with clinically significant laboratory abnormalities in hematology, chemistry and urinalysis 
parameters will be summarized for low and high categories by treatment group. 
Shift tables from baseline grade to post-baseline highest grade will be presented for clinical laboratory 
measurements (serum chemistry and hematology) by treatment group. Shift tables for urinalysis will be 
presented by normal, abnormal based on the investigator-assessed clinically significant laboratory 
abnormalities. 
All data will be all displayed in subject data listings for all safety subjects. 
7.7.4 
Vital Signs 
Descriptive statistics will be prepared for vital signs value at visit and change from baseline.   
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Statistical Analysis Plan 
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7.7.5 
Other Safety Assessments 
Concomitant medications (especially medications used for bone pain), ECG, physical examination, 
pregnancy test, abdominal ultrasound, chest x-ray and TB test results will be presented in listings for all 
Safety subjects. 
8. 6-MONTH LONG-TERM FOLLOW-UP ANALYSES  
Database lock and data analyses will occur after all subjects have completed the End-of-Treatment visit 
21 days after the last dose of study drug, with the exception of the long-term follow-up visit at 6 months 
after last dose of study drug. No inferential analysis is planned prior to database lock.  Database lock and 
data analyses including the long-term follow-up visit will be analyzed and reported subsequently once all 
data for these assessments are completed. 
9. CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
No changes are planned from the protocol. 
10. STATISTICAL SOFTWARE 
All analyses will be done using SAS version 9.4. 
11. REFERENCES 
1. Dmitrienko, A., Tamhane, A.C. and Bretz, F. (2009), Multiple Testing Problems in 
Pharmaceutical Statistics, Boca Raton, FL: Taylor & Francis/CRC Press. 
2. Dmitrienko, Offen, Westfall. (2003). Gatekeeping strategies for clinical trials that do not require 
all primary effects to be significant. Statistics in Medicine. 22, 2387-2400. 
3. Marcus R, Peritz E, Gabriel KR. (1976). On closed testing procedure with special reference to 
ordered analysis of variance. Biometrika. 63, 655-660. 
4. Westfall, Krishen. (2001). Optimally weighted, fixed sequence, and gatekeeping multiple testing 
procedures. Journal of Statistical Planning and Inference. 99, 25-40 
5. Wiens BL, Dmitrienko A. The fallback procedure for evaluating single family of hypotheses. J 
Biopham Stat. (2005);15(6):929-42 
6. U.S Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) Draft 
Guidance, Multiple Endpoints in Clinical Trials, Guidance for Industry. January 20017. 
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Statistical Analysis Plan 
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APPENDIX 1  DATA HANDLING RULES 
Category 
Description 
Data Handling Rules 
Demographics 
Age (years) 
Age = integer((date of screening-date of birth)/365.25)   
Demographic 
BMI 
BMI = Weight(kg) / [Height(cm)/100*Height(cm)/100] 
Demographic 
BSA 
BSA =( [Height(cm) x Weight(kg) ]/ 3600 )1/2 
Demographic 
Days from 
diagnosis 
Days from diagnosis = Date of randomization – Date of 
diagnosis 
Medical 
History 
Any Medical 
history 
flags are none, but data are present, change the flag to “Yes” 
Efficacy 
Duration in days of 
Grade 4 
neutropenia 
= Date of last day in cycle’s first 12 days with ANC < 0.5 × 109/L – 
 Date of first day in cycle’s first 12 days with ANC < 0.5 × 109/L + 
1 
Efficacy 
Incident Rate (%) 
Incident rate (%) = 100% × (Number of subjects with at least one 
x/Total number of subjects with post-baseline ANC value) 
Efficacy 
ANC Recovery 
=(Date when ANC ≥ 2.0 × 109/L) – (Date of nadir in this cycle) + 1 
Safety Lab 
Assessment day 
Assessment day = (Date of assessment) – (Date of first 
chemotherapy) + 1. 
Safety Lab 
Change from 
baseline 
Change from baseline = Current Value – Value at last assessment 
prior to Cycle 1 chemotherapy treatment. 
APPENDIX 2  SAS CODE FOR STATISTICAL ANALYSES 
This section is presented in a separate document prior to the final signoff of this SAP.   
 
APPENDIX 3  MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) 
Mockup tables, listings, and graphs are presented in a separate document prior to the final signoff of this 
SAP. 
 
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