A Phase III, Randomized, Multi-Centre, Double-Blind, Placebo Controlled Clinical Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy
Phase: PHASE3
Conditions: Breast Cancer, Neutropenia
Sponsor: EVIVE Biotechnology

rp 
Clinical and Regulatory Affairs, Generon (Shanghai) Corporation 
Building 9, 787 Kang Qiao Road, Shanghai, PRC 201315 
Study Title: 
Study Number: 
Study Phase: 
Product Name: 
IND Number: 
Indication: 
Investigators: 
Sponsor: 
Sponsor Contact & 
Medical Monitor: 
Name of Principal 
Investigators: 
Protocol Date: 
Protocol: GC-627-04 
Date: 07 May 2017 
Tel: 8621-61760866 Fax: 8621-61760865 
Clinical Study Protocol: GC-627-04 
A Phase III, Randomized, Multi-Centre, Double-Blind, Placebo 
Controlled Clinical Trial of F-627 in Women with Breast Cancer 
Receiving Myelotoxic Chemotherapy 
GC-627-04 
III 
F-627-
Myelotoxic Chemotherapy fuduced Neutropenia 
Multicenter 
Generon (Shanghai) Corporation 
Building 9, 787 Kang Qiao Road, 
Shanghai, PRC 201315 
Tel: 8621-61760866 
Fax: 8621-61760865 
Kai yang (Tom) Tang, MD 
Regulatory and Clinical Affairs 
Building 9, 787 Kang Qiao Road, 
Shanghai, PRC 201315 
Tel: 8621-61760866 
Fax: 8621-61760865 
Dr. John Glaspy, 
UCLA 
07 May2017 
Version: Amendment 1.0 
Proprieta1y and Confdential 
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INTRODUCTORY AND CONFIDENTIALITY STATEMENT 
 
This protocol has been prepared according to the ICH Harmonized Tripartite Guidelines for 
Good Clinical Practice issued in June 1996, with an implication date of January 17, 1997 and 
FDA GCP guidelines: 21 CFR 312, 21 CFR 50, 21 CFR 56.  
 
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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Sponsor’s Medical Expert for the Trial:  
 
Kaiyang (Tom) Tang, MD, MBA 
Chief Medical Officer, Clinical and Regulatory Affairs 
Generon (Shanghai) Corporation Ltd. 
Building 9, 787 Kang Qiao Road 
Shanghai, China 201203 
 
Sponsor Approvals: 
 
Kaiyang (Tom) Tang, MD, MBA 
Chief Medical Officer, Clinical and Regulatory Affairs  
Generon (Shanghai) Corporation Ltd. 
 
 
 
 
                                 May 07, 2017               
…………………………………. 
 
 
………………………………. 
Signature  
 
 
 
 
 
 
 
Date 
 

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STUDY SYNOPSIS 
Protocol Number: 
GC-627-04 
Title: 
A Phase III, Randomized, Multi-Centre, Double-Blind, Placebo 
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: 
Myelotoxic Chemotherapy Induced Neutropenia 
Sponsor: 
Generon (Shanghai) Corporation  
Building 9, 787 Kang Qiao Road, 
Shanghai, PRC 201315 
Tel: 8621-61760866 
Fax: 8621-61760865 
Name of Sponsor 
Contact: 
Kaiyang (Tom) Tang, MD 
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. 
Concurrent Control: 
Placebo   
Objectives and Study 
Endpoints: 
Objective:  
The objective of the study is to evaluate the efficacy and safety of F-627 
given as a single fixed dose pre-filled syringe in the subject’s first 
chemotherapy cycle in comparison to Placebo.  
 
Safety Endpoints: 
1. Adverse event reporting. 
2. Vital sign measurements. 
3. Laboratory measurements. 
4. ECG Measurements. 
5. Physical Examination. 
Primary Efficacy Endpoint: 
The primary endpoint will be the duration of grade 4 (severe) 
neutropenia (ANC < 0.5 x 109/L) observed in chemotherapy cycle 1.  
 
 

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administered Day 2 of each of the following 3 chemotherapy cycles. 
Randomization will occur in a 2:1 (Arm 1:Arm 2) ratio using a central 
randomization system (IWRS) on Day 1 of the first chemotherapy cycle. 
A central lab will conduct all ANC measurements used for analysis, 
however local lab ANC values may be used if central lab samples are 
compromised in quality.  Local Labs maybe used to monitor subject 
safety during the course of the study. 
Subjects randomized to Arm 2, Placebo study arm for chemotherapy 
Cycle 1, will be dosed with F-627 for each of the following 3 
chemotherapy cycles. Subjects will return for a final study visit 3 weeks 
after the final study drug administration.  
A 12-lead ECG at baseline, before each subsequent dose, and at the end 
of study.  A Central ECG laboratory utilizing blinded ECG readers will 
be employed to control variability and bias in interpretation. 
Study Sites: 
This study will be conducted in up to 30 clinical centers in North 
America and Europe  
Subject Population: 
The study population will consist of approximately 120 female subjects ≥ 
18 to ≤ 75 years of age diagnosed with Stage II-IV breast cancer. 
Eligibility: 
Subjects are eligible for study entry if they meet the following inclusion 
criteria: ≥ 18 and ≤ 75 years of age; diagnosis Stage II-IV breast cancer 
in the adjuvant or metastatic setting; 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; scheduled for 
chemotherapy. Patients 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 if they have 
undergone a bone marrow or stem-cell transplantation.   
Subjects with a history of prior malignancy other than breast cancer may 
enter the study if the malignancy is in remission and not receiving active 
treatment.  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 
in addition to a 14 day screening phase. 
Subjects will be dosed according to their Treatment Arm randomized on 
Day 1 of chemotherapy Cycle 1. Subjects randomized to Placebo study 
arm for chemotherapy Cycle 1 will be dosed with F-627 for each of the 
following 3 chemotherapy 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 more 
than 4 x 109/L and platelet count more than 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 24 hours after 

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chemotherapy administration for study drug dosing.  This will typically 
occur on study days 2, 23, 44 and 65 but may differ slightly as the actual 
time frame will be dependent upon the subject’s individual chemotherapy 
schedule, as noted above. 
For the first chemotherapy cycle, study subjects are required to return to 
the study site for daily blood draws to track ANC behavior post 
chemotherapy until ANC levels reach ≥ 2.0 × 109/L, post-nadir and then 
three days later. 
Chemotherapy Cycles 2, 3, 4:   
Subjects are required to return 24 hours after chemotherapy 
administration for study drug dosing.  For cycles 2, 3, 4, subjects are 
required to return every other day to the study site for blood draws to 
track ANC behavior post chemotherapy until 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, a daily ANC blood draw 
must be done until the ANC level is > 0.5 × 109/L. 
If patient’s ANC < 0.5 × 109/L for more than 6 consecutive days in that 
chemotherapy cycle, a rescue therapy maybe initiated based on 
investigators discretion.    
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 Day 2 of 
each of 4 chemotherapy cycles. 
Arm 2: Placebo, pre filled syringe, administered Day 2 of the first 
chemotherapy cycle.  F-627, 20 mg fixed dose pre filled syringe 
administered Day 2 of each of following 3 chemotherapy cycles. 
Sample Size:  
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 in the first 
chemotherapy cycle as compared to Placebo. The primary endpoint will 
be the duration of severe neutropenia (ANC < 0.5 x 109/L) observed in 
chemotherapy cycle 1.  
Assuming an expected difference in the duration of severe neutropenia 
for F-627 as compared to Placebo of 2.0 days, with a common standard 
deviation of 3 days, this Phase III global clinical study will randomize 
approximately 120 subjects in a 2:1 ratio to Arm 1 (F-627 in all 
chemotherapy cycles) and Arm 2 (Placebo in Cycle 1, and F-627 in the 
following 3 chemotherapy cycles) respectively. The dropout rate for the 
trial is assumed to be 10%. Under these assumptions, enrollment of 80 
subjects for the F-627 arm and 40 subjects for the Placebo arm for Cycle 
1 would be required to realize 90% power. 
Efficacy Assessments: 
Evaluation of efficacy of F-627 given as a single fixed dose (20 mg) pre-
filled syringe in the first chemotherapy cycle in comparison to Placebo 
by means of a subject’s ANC. 
Safety Assessments: 
• 
AEs and SAEs 
• 
Vital signs 
• 
Clinical laboratory tests (to include hematology, serum chemistry, 
and urinalysis)  

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• 
ECG assessments (to include heart rate, PR, QRS and QTcF 
intervals, and T-wave morphology)  
• 
Physical Examination 
Data Analyses: 
• 
Primary efficacy analysis will be evaluated as a comparison of the 
duration of severe neutropenia (ANC < 0.5 x 109/L) observed in 
chemotherapy cycle 1 between Arm 1 and Arm 2. 
• 
Safety analysis will be assessed by a review of all safety parameters 
including adverse events (AEs), laboratory safety parameters, vital 
signs and physical examination. 

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Table of Contents 
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 ............................................................... 14 
2.3 
Description and Justification for Route of Administration, Dosage and Regimen, and 
Treatment Period ...................................................................................................................... 17 
2.3.1 
Route of Administration ............................................................................................... 17 
2.3.2 
Justification for Clinical Dose ...................................................................................... 17 
2.3.3 
Dosage Regimen........................................................................................................... 18 
2.4 
Study Conduct ........................................................................................................................... 18 
2.5 
Study Population ........................................................................................................................ 18 
3 
TRIAL OBJECTIVES AND ENDPOINTS ......................................................................................... 19 
3.1 
Primary Efficacy Objective ....................................................................................................... 19 
3.2 
Primary Efficacy Endpoint ........................................................................................................ 19 
3.3 
Secondary Efficacy Endpoints ................................................................................................... 19 
3.4 
Safety Objective ......................................................................................................................... 19 
3.5 
 ................................................................................................................ 20 
4 
TRIAL DESIGN AND RATIONALE ................................................................................................. 21 
4.1 
Trial Design ............................................................................................................................... 21 
4.2 
Rationale .................................................................................................................................... 22 
4.3 
Schematic Diagram and Trial Design ........................................................................................ 23 
5 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................................................ 24 
5.1 
Subject Inclusion Criteria .......................................................................................................... 24 
5.2 
Subject Exclusion Criteria ......................................................................................................... 24 
5.3 
Subject Withdrawal from Study ................................................................................................ 25 
5.3.1 
Criteria for Subject Withdrawal ................................................................................... 25 
5.3.2 
Procedures for Subject Withdrawal .............................................................................. 26 
5.3.3 
Replacements for Withdrawn Subjects ........................................................................ 26 
5.3.4 
Follow-Up of Withdrawn Subjects ............................................................................... 26 
5.3.5 
Documentation ............................................................................................................. 26 
6 
TRIAL PROCEDURES ....................................................................................................................... 27 
6.1 
Measures to Avoid Bias ............................................................................................................. 27 
6.1.1 
Randomization.............................................................................................................. 27 
6.1.2 
Simultaneous Utilization of All Arms .......................................................................... 27 
6.2 
Trial Treatment and Dosage and Regimen of Investigational Products .................................... 27 

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6.2.1 
Treatment Dose ............................................................................................................ 27 
6.2.2 
Description of the Dosage Form, Packaging and Labeling of the 
Investigational Product ............................................................................................... 27 
6.2.3 
Investigational Dose Schedule ..................................................................................... 28 
6.3 
Duration of Subject Participation .............................................................................................. 28 
6.4 
Hold and Stop Rules .................................................................................................................. 28 
6.4.1 
Stop Rules for Subjects (Study Drug Discontinuation) ................................................ 28 
6.4.2 
End of Treatment and Follow-up Visits ....................................................................... 29 
6.5 
Unblinding ................................................................................................................................. 29 
6.6 
Accountability Procedures ......................................................................................................... 29 
6.7 
Electronic Case Report Forms ................................................................................................... 30 
7 
TREATMENT OF SUBJECTS ............................................................................................................ 30 
7.1 
Dosing ........................................................................................................................................ 30 
7.2 
Concomitant Medications .......................................................................................................... 30 
7.3 
Approved Medications ............................................................................................................... 30 
7.4 
Medications Not Permitted ........................................................................................................ 30 
7.5 
Compliance ................................................................................................................................ 31 
8 
ASSESSMENT OF EFFICACY .......................................................................................................... 31 
8.1 
Efficacy Parameters ................................................................................................................... 31 
9 
ASSESSMENT OF SAFETY .............................................................................................................. 32 
9.1 
Safety Parameters ...................................................................................................................... 32 
9.1.1 
Standard Safety Parameters .......................................................................................... 32 
9.2 
The Methods and Timing for Assessing, Recording and Analyzing Safety Parameters ........... 32 
9.2.1 
Medical History and Clinical Signs and Symptoms ..................................................... 32 
9.2.2 
Physical Examination ................................................................................................... 32 
9.2.3 
ECG Measurement ....................................................................................................... 32 
9.2.4 
Reporting ...................................................................................................................... 33 
9.3 
Procedures for Eliciting Reports of and Recording and Reporting Adverse Events and 
Intercurrent Illnesses ................................................................................................................. 33 
9.4 
Type and Duration of Follow-Up of Subjects after Adverse Events ......................................... 33 
9.5 
Defining, Grading and Reporting Adverse Events .................................................................... 33 
9.5.1 
Adverse Events ............................................................................................................. 33 
9.5.2 
Definition ..................................................................................................................... 34 
9.5.3 
Serious Adverse Events ................................................................................................ 34 
9.5.4 
Grading Adverse Events ............................................................................................... 35 
9.5.5 
Exposure in Utero ......................................................................................................... 36 
9.5.6 
Relationship to Study Therapy ..................................................................................... 37 
9.5.7 
Abnormal Laboratory Findings .................................................................................... 38 
9.5.8 
Eliciting Adverse Event Information............................................................................ 39 
9.5.9 
Reporting Requirements (Serious and Non-Serious) ................................................... 39 
10 STATISTICAL ANALYSIS ............................................................................................................... 40 

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10.1 Study Endpoints ........................................................................................................................ 41 
10.1.1 
Primary Efficacy Endpoint ......................................................................................... 41 
10.1.2 
Secondary Efficacy Endpoints ................................................................................... 41 
10.1.3 
Safety Analysis ........................................................................................................... 41 
10.2 Statistical Methods.................................................................................................................... 41 
10.2.1 
Efficacy Analysis ....................................................................................................... 42 
10.2.2 
Primary Efficacy Analysis .......................................................................................... 42 
10.2.3 
Secondary Efficacy Analysis ...................................................................................... 42 
10.2.4 
Safety Analysis ........................................................................................................... 43 
10.2.5 
Sample Size Calculation ............................................................................................. 44 
10.3 Criteria for Termination and Sponsor Discontinuation Criteria ............................................... 44 
10.4 Procedure for Accounting for Missing, Unused and Spurious Data ......................................... 45 
10.5 Procedure for Reporting Deviations from the Original Statistical Plan and Justification ........ 45 
10.6 Selection of Subjects Included in the Analysis ......................................................................... 45 
10.6.1 
Safety Analyses Set .................................................................................................... 45 
10.6.2 
Intent to Treat Analysis Set ........................................................................................ 45 
10.6.3 
Per Protocol Analysis Set ........................................................................................... 45 
11 DIRECT ACCESS TO SOURCE DOCUMENTS ............................................................................. 45 
12 QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 46 
13 ETHICS ............................................................................................................................................... 46 
13.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ................................ 46 
13.2 Ethical Conduct of the Trial ..................................................................................................... 46 
13.3 Patient Information and Consent .............................................................................................. 47 
14 DATA HANDLING AND RECORD KEEPING ............................................................................... 47 
14.1 Electronic Case Report Forms (eCRFs).................................................................................... 47 
14.2 Record Retention ...................................................................................................................... 48 
15 FINANCING AND INSURANCE ..................................................................................................... 48 
16 PUBLICATION POLICY ................................................................................................................... 48 
17 REFERENCES .................................................................................................................................... 48 
18 APPENDICES .................................................................................................................................... 51 
18.1 Trial Procedures and Activities ................................................................................................ 51 
18.2 Study Flow Chart ...................................................................................................................... 54 
18.3 Central Lab Locations............................................................................................................... 55 
18.4 Definition of Abbreviations and Definitions of Terms ............................................................. 56 
 
 
 
 
 
 

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1 PROTOCOL IDENTIFIERS 
 
 
 
 
 
Therapeutic area: 
Oncology 
Product: 
F-627 
Indication: 
Neutropenia 
Title of Study: 
A Phase III, Randomized, Multi-Centre, Double-Blind, Placebo 
Controlled Clinical Trial of F-627 in Women with Breast 
Cancer Receiving Myelotoxic Chemotherapy 
FDA IND # 
 

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2 BACKGROUND INFORMATION 
 
2.1 Name and Description of Investigational Product 
2.1.1 Characteristics and Description  
The F-627 phase III clinical drug product is supplied in a prefilled syringe (PFS) 
containing 20.0 mg F-627 as a sterile, single use, preservative free solution for 
convenient subcutaneous injection. 
2.1.2 Physical and Chemical Characteristics of the Drug Substance  
F-627 is a recombinant fusion protein consisting of human G-CSF and human IgG2 
Fc fragments. F-627 is glycosylated with a molecule weight of approximately 93.4 
kDa and is produced in Chinese Hamster Ovary (CHO) cells and is produced via a 
cell culture process in a serum free medium (containing no animal products) 
followed by a series of purification steps. F-627 is manufactured according to Good 
Manufacturing Practice (GMP) for Pharmaceutical Products, 1998. The test 
procedure and acceptance criteria followed ICH Guideline, Q6B, 1999. 
  
2.2 Studies and Findings  
2.2.1 Non-Clinical Studies  
F-627 exhibits pharmacological effects in a dose-dependent manner in vitro and in 
vivo. Similar to the existing recombinant human granulocyte CSFs (rhG-CSFs), F-
627 was able to stimulate neutrophil production in normal and neutropenic animals. 
For cyclophosphamide (CP)-induced neutropenia in monkeys, F-627 generated faster 
neutrophil recovery and reduced the severity of neutropenia when compared to 
Filgrastim and Pegfilgrastim (1).  
 
F-627 exhibits non-linear pharmacokinetic (PK) properties. A correlation of 
pharmacokinetic/pharmacodynamic (PD) responses was demonstrated in rats and 
monkeys(1). 
 
Preclinical safety studies were conducted including safety pharmacology studies, 
single dose acute toxicity studies in rats and monkeys, repeat dosing 3-month 
toxicity studies in rats and monkeys, and a series of local tolerance tests to determine 
the clinical formulation. The safety profile for F-627 was established in these studies. 
In the 3-month repeated dose toxicity studies that had weekly subcutaneous 
injections, the No Observable Adverse Effect Levels (NOAELs) were determined to 
be 1,000 µg/kg in rats and 675 µg/kg in monkeys.  
 

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The Phase I clinical study in healthy male subjects demonstrated that F-627 was well 
tolerated at doses up to 
. Favorable PK 
properties and dose-dependent PD response 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 this study was to evaluate the efficacy of the 
F-627 given as a 
 
μ
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 (Taxotere® 
+ cyclophosphamide) or TAC (Taxotere® + doxorubicin + cyclophosphamide). 
Myelotoxicity in this 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 are recommended. 
 
Safety results of GC-627-02 
The overall rates of AEs, SAEs, FN, injection site reactions, and laboratory values 
for F-627 doses were lower or similar to those for pegfilgrastim in this study. No 
differences in laboratory values between treatment groups were apparent. 
Further studies are required to fully examine the safety profile of F-627 in cancer 
patients.  
 
In addition a Phase II study, SP-CDR-1-1302, was conducted to examine the two 
fixed doses of F-627.  This study was an active-controlled, dose-finding study that 
demonstrated F-627 to be statistically non-inferiority to Filgrastim for two fixed 
doses of F-627 
 the duration of moderate and severe 
neutropenia.   The ANC profiles were comparable between the F-627 doses
 
 and the standard dose of Filgrastim.  
 

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3 TRIAL OBJECTIVES AND ENDPOINTS 
 
3.1 Primary Efficacy Objective 
The objective of the study is to evaluate the efficacy and safety of F-627 given as a single 
fixed dose pre-filled syringe in the subject’s first chemotherapy cycle in comparison to 
Placebo.  
3.2 Primary Efficacy Endpoint 
The primary efficacy endpoint of the study will be the duration of grade 4 (severe) 
neutropenia (ANC < 0.5 x 109/L) observed in chemotherapy cycle 1.  
 
3.3 Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study are as follows: 
 
 
The duration in days of grade 4 (severe) neutropenia (ANC < 0.5 × 109/L) for 
chemotherapy cycles 2, 3, and 4, and over all cycles. 
 
The duration in days of grade 2 (mild, ANC < 1.5 × 109/L) and 3 (moderate, ANC < 
1.0 × 109/L) neutropenia () for each chemotherapy cycle and over all cycles.  
 
The incidence rates of febrile neutropenia (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 
× 109/L) for each chemotherapy cycle. 
 
The incidence rates of grade 2, grade 3, and grade 4 neutropenia for all chemotherapy 
cycles. 
 
The time in days to ANC recovery post nadir for each chemotherapy cycle and over 
all cycles; recovery is defined as an ANC ≥ 2.0 × 109/L after the expected ANC nadir. 
 
The depth of the ANC nadir for each chemotherapy cycle and over all cycles.  
 
The incidence rates of infections for each chemotherapy cycle and over all cycles. 
 
The use of antibiotic and pain medications for each chemotherapy cycle and over all 
cycles. 
 
ECG endpoints: Change-from-baseline heart rate, PR, QRS and QTcF intervals. 
Categorical outliers and T-wave morphology changes on treatment. 
 
 
3.4 Safety Objective 
• To assess safety in patients treated with the a fixed dose of F-627 identified in this 
protocol using the AE/SAE reporting, and other standard lab findings including 
hematology and blood chemistry, urinalysis, and symptoms including, but not limited 
to, bone and back pain. 
 

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4 TRIAL DESIGN AND RATIONALE  
 
4.1 Trial Design  
This Phase III, global, two arm, double-blinded clinical study will randomize 
approximately 120 subjects with Stage II - IV breast cancer in the adjuvant or metastatic 
setting, who are to receive myelotoxic TA chemotherapy treatment (docetaxel + 
doxorubicin, 75 and 60 mg/m2, respectively). The 120 subjects will be randomized in a 2:1 
ratio of F-627 and Placebo, respectively. The dropout rate for the trial is assumed to be 
10%. Under these assumptions, enrollment of 80 subjects for the F-627 arm and 40 
subjects for the Placebo arm for Cycle 1 would be required to realize 90% power. 
The patient population in this study is similar to the studies conducted by Jones et al (3),(4).  
Subjects in this study will be those who are scheduled to undergo at least 4, 21-day cycles 
TA (docetaxel and doxorubicin 75 and 60 mg/m2) chemotherapy. 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.  Subjects maybe scheduled for more than 4 cycles 
of chemotherapy, however, study participation will be limited to a subject’s first 4 cycles.  
Since all subjects will receive F-627 from cycle two, chemotherapy dose reduction at cycle 
two should be carefully evaluated. The design is similar to the Phase III trial conducted 
with Neulasta® (Neulastim®, pegfilgrastim) (5-7). 
The screening period for this trial is approximately 14 days.  During this time the subject 
will be consented and then evaluated for study eligibility via the study screening tests. 
Qualified subjects will be randomized to one of two arms in a 2:1 ratio (F-627:Placebo in 
Cycle 1) using a central randomization system (IWRS) on Day 1 of the first chemotherapy 
cycle.   Each randomized subject will have 12-lead ECG measurements will be performed 
at baseline, prior to study drug dosing and at the end of study.  The ECGs will be centrally 
read by a blinded team of readers. 
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 administered Day 2 of each of 4 
chemotherapy cycles. 
Arm 2: Placebo, fixed dose pre filled syringe administered Day 2 of the first chemotherapy 
cycle, and F-627, 20 mg fixed dose pre filled syringe administered Day 2 of each of the 
following 3 chemotherapy 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, WBC more 
than 4 x 109/L and platelet count more than 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:  

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For the first chemotherapy cycle, study subjects are required to return to the study site for 
daily blood draws to track ANC behavior post chemotherapy until ANC levels reach ≥ 2.0 
× 109/L, post-nadir and then three days later. 
Chemotherapy Cycles 2, 3, 4:   
Subjects are required to return 24 hours after chemotherapy administration for study drug 
dosing.  For cycles 2, 3, 4, subjects are required to return every other day to the study site 
for blood draws to track ANC behavior post chemotherapy until 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, a daily ANC blood draw must be done until 
the ANC level is > 0.5 × 109/L. 
Subjects will return for a final study visit 3 weeks after the final study drug administration. 
Any AEs should be noted and followed to resolution or stabilization. 
 
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 (8),(9). The first 
generation rhG-CSF, filgrastim, received FDA approval in the US in 1991 for treating 
neutropenia (10-12). 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 rmetHuG-CSF, pegfilgrastim, which received 
FDA approval in 2002 (13).  Pegfilgrastim has an extended half-life of 30 to 80 hours and 
requires less frequent administration than filgrastim and lenograstim (14-16).  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, while a higher 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 (17).  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 to cancer patients by shortening the duration and lessening the 
severity of chemotherapy-induced neutropenia. Thus, F-627 could be used to better 
manage severe neutropenia, which would fulfill an unmet medical need.  
 
 
 
 

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4.3 Schematic Diagram and Trial Design 
 
 
Stage II-IV Breast Cancer 
Patients (TA) 
Cycle 1, Day 1  
TA Chemotherapy 
F-627 (20mg) or Placebo Randomization (2:1) 
Cycle 1, Day 2  
F-627 20 mg SC 
N=80 
Cycle 1, Day 2  
Placebo, SC 
 N=40 
 Cycles 2-4 
TA Chemotherapy 
F-627 20 mg SC 
N=80 
 Cycles 2-4 
TA Chemotherapy 
F-627 20 mg SC 
N=40 

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5 SELECTION AND WITHDRAWAL OF SUBJECTS 
 
5.1 Subject Inclusion Criteria 
1) Show evidence of a personally signed and dated informed consent document indicating 
that the patient has been informed of all pertinent aspects of the trial.  
2) Females ≥ 18 years of age and < 75 years of age. 
3) Diagnosed with Stage II-IV breast cancer. 
4) Subject is scheduled to undergo 4 cycles of TA chemotherapy (docetaxel, doxorubicin, 
75, and 60 mg/m2, respectively).  
5) ECOG Performance status of ≤ 2. 
6) White Blood Cell count (WBC) ≥ 4.0 × 109/L, hemoglobin ≥ 11.5 g/dL and a platelet 
count ≥ 150 × 109/L. 
7) 
Demonstrate adequate renal, hepatic function (Liver function tests (ALT, AST, 
alkaline phosphatase and total bilirubin)) should be less than 2.5x upper limits of 
normal (ULN). Serum creatinine should be less than 1.7x ULN.  
8) 
All subjects must agree to use at least one of the following types of contraception: 
intrauterine device, implantable progesterone device, progesterone intramuscular 
injection, or oral contraceptive, which has been started at least one month prior to visit 
one and will continue for the duration of the trial.  The contraceptive patch or condom 
use with spermicide is also an acceptable form 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 or ≥ 75 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 365 days of screening. 
8) Subject has documented congestive heart failure, cardiomyopathy or myocardial 
infarction by clinical diagnosis, ECG test, or any other relevant test. 
9) History of alcohol or drug abuse that would interfere with the ability to be compliant 

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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. 
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 ≥ 2.5 upper limit of normal. 
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) 
Any uncontrollable grade 3 or 4 AE that the investigator believes is possibly 
related to study drug. 
3) 
Failure to comply with protocol requirements.  
4) 
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.  
5) 
Subjects with a positive pregnancy test, such as a positive beta HCG. 
6) A subject who experiences any uncontrolled infection requiring antibiotics 
and/or hospitalization. 
7) 
Death of the subject.  

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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 study assessment.   
 
5.3.3 Replacements for Withdrawn Subjects 
Subjects dropping out during the first treatment cycle will be replaced. Subjects 
dropping out post cycle 1 will not be replaced. 
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.  
We ask and encourage that the results from any antibody tests performed for the 
evaluation of antibody development to GCSF compounds as related to F-627.  If the 
subject allows, this follow up visit can be performed via phone call. 
 
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).  

 
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6 TRIAL PROCEDURES 
 
See Section 18.1 and 18.2 (Study Flow Chart). 
  
6.1 Measures to Avoid Bias  
6.1.1 Randomization 
This study is a double blind study for the first cycle of chemotherapy.  Eligible 
subjects in this study will be randomized to either F-627 20 mg/dose or Placebo in a 
2:1 ratio, respectively in Cycle 1.  Treatment randomization will be stratified by 
country/region. All subjects will be placed on the F-627 study drug for the following 
3 chemotherapy cycles.  An interactive web-based response system (IWRS) with a 
24-hour live support Helpdesk will be used in the study. Authorized study site 
personnel will access the randomization system using a user ID and password. Prior 
training and a user’s manual will be provided to all the study participating sites. 
 
6.1.2 Simultaneous Utilization of All Arms 
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 subcutaneously 24 hours after receiving TA chemotherapy.  
Subjects will be dosed with either the F-627 20mg/dose fixed dose pre filled syringe 
or placebo in the first chemotherapy cycle, depending on the randomization arm 
assigned. All subjects will receive the F-627 20mg/dose fixed dose pre filled syringe 
for chemotherapy cycles 2-4.  A subject’s chemotherapy dosing regimen should 
remain unchanged for the first two chemotherapy cycles. 
 
 
6.2.2 Description of the Dosage Form, Packaging and Labeling of the Investigational 
Product  
Each site will receive enough F-627 drug kits and enough placebo kits for their 
subjects for the duration of the clinical trial.  Each F-627 kit will contain one 
prefilled syringe (PFS) containing 20.0 mg F-627 as a sterile, single use, preservative 
free solution for convenient subcutaneous injection. Each placebo kit will consist of 
an identical model prefilled syringe with saline.  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.  

 
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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 Investigational 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 at approximately 24 
hours after the chemotherapy treatment is administered. 
 
6.3 Duration of Subject Participation  
Prior to randomization, there is a screening period of up to two weeks 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. 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, WBC of more than 4 x 109/L and platelet count more than 100 x 109/L.   
 
6.4 Hold and Stop Rules 
6.4.1 Stop Rules for Subjects (Study Drug Discontinuation)  
Any hospitalization, serious uncontrolled infection requiring antibiotics, possibly drug 
related SAE, or demonstrated drug hypersensitivity is cause for subjects to discontinue 
drug if the investigator feels it is appropriate.  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.  

 
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Since subjects maybe randomized to the placebo arm for their first chemotherapy 
cycle, their ANC level should be monitored closely. If a subject’s ANC is < 0.5 × 
109/L for more than 6 days during that chemotherapy cycle or the subject develops 
febrile neutropenia, a rescue therapy maybe initiated at the investigators discretion. 
The subject maybe considered discontinued/withdrawn from the study if the rescue 
therapy includes a short acting GCSF.  Any use of concomitant medication should be 
documented and the subject’s ANC level should be closely monitored until recovered. 
 
6.4.2  End of Treatment and Follow-up Visits 
All subjects will receive an end of study assessment on Day 84 (or 3 weeks after the 
patient’s last dose of investigational agent).  All adverse events will be followed until 
stabilization or resolution. Note: these dates are approximate as they are dependent 
upon an individual’s chemotherapy treatment schedule. 
6.5 Unblinding 
If a serious and life-threatening adverse event occurs and determination of subject 
treatment arm is required, the regional medical monitor must be contacted and notified of 
the event immediately. This study is a placebo controlled double blind study for a 
subject’s first chemotherapy cycle only.  A subject will receive F-627 for their following 
three chemotherapy cycles.  If Investigators have a subject with a serious and life-
threatening adverse event, the Investigator should request the medical monitor to unblind 
the subject via the IWRS. It is recommended that subjects are not in general unblinded for 
febrile or severe neutropenia as this is an expected event, which should be controlled by 
rescue therapy.  Investigators will, however, have the ability to un-blind patient treatment 
via the IWRS for emergency purposes.  For all other events that may require un-blinding 
of the subject treatment assignment, the medical monitor must be contacted before any un-
blinding occurs. In all cases, the regional medical monitor will notify the Sponsor 
immediately. The Investigator or the regional medical monitor may carry out emergency 
un-blinding through the IWRS only. 
 
The subject is considered discontinued from the study after un-blinding. The safety will be 
followed until it is resolved. There will be no replacement of discontinued subjects due to 
un-blinding. 
6.6 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 site 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 procedures or requirements.  
 

 
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6.7 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 EDC system iDataFax 4.3. 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 
Subcutaneous 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.  Chemotherapy dosage should remain unchanged for the first two 
chemotherapy cycles. 
7.2 Concomitant Medications  
Concomitant medications are permitted as deemed appropriate by the investigator. 
 
7.3 Approved Medications 
Any FDA approved prescription medication may be given as needed, including those 
necessary to treat symptoms 
7.4 Medications Not Permitted 
F-627 is similar to Neulasta® (Neulastim®, pegfilgrastim), which is another type of long 
acting GCSF, and stimulates neutrophil production in vivo.   No formal drug interaction 
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drugs specifically contraindicated for this study, however, any type of long acting GCSF is 
prohibited.  Short acting G-CSF drugs are not permitted during the normal course of the 
study, however, a short acting G-CSF maybe used if rescue therapy is needed due to the 
development of febrile neutropenia or prolonged severe neutropenia (>6 days). If short 
acting GCSF being used, it should be documented as a concomitant medication and 
recorded in the study eCRFs. Drugs such as lithium may potentiate the release of 
neutrophils and thus are not permitted in this study. 
 
7.5 Compliance 
Subject compliance will be monitored by reviewing the study medication accountability 
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 
The primary efficacy parameter will be the duration of grade 4 neutropenia (ANC < 0.5 x 
109/L) observed in chemotherapy cycle 1. 
Secondary efficacy parameters will include the duration of grades 2, 3 and  4 neutropenia 
(ANC < 1.5 × 109/L, ANC < 1.0 × 109/L, ANC < 0.5 x 109/L, respectively) 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 results 
may be used in instances where the central lab results are unavailable or have been 
compromised due to sample quality. 
 

 
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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. 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) v 4.03 will be used to grade potential adverse events.  
 
Local blood samples will be used to determine the status of a subject’s ANC level 
for local safety monitoring and local evaluation.  Locally determined ANC values 
can be used in instances where the central lab value is unavailable or 
compromised due to sample quality. 
 
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 adverse events data will be 
collected. If other unscheduled activities are performed, such as physical 
examination or laboratory studies, the results must be provided on the electronic 
case report forms (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. 
9.2.3 
ECG Measurement 
 
A standard 12-lead ECG should be obtained using equipment provided by the 
sponsor.  The ECG will be obtained after the subject has been in a semi-
recumbent position for approximately 10 minutes at the following times: 
screening, prior to each administration of study drug dose, and at the end of study. 
For each 12 Lead ECG procedure, the designated iCardiac study cardiologist will 
provide a comprehensive diagnostic interpretation along with evaluation and 
confirmation of the semi-automated interval analysis. (QT, QTcF, RR, PR, QRS, 
HR), and T and U wave assessment. Reading and interpretation of the ECG will 
be performed centrally and provided to the investigator.  The investigator is 

 
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responsible for reviewing interpretations and for retaining hard copies of the 
reports.  
 
9.2.4 
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 adverse events 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 
Subjects will have their last study visit (Day 84) and all adverse events occurring since the 
last study drug dose should be identified and recorded.   Any grade 3 or 4 adverse events or 
serious adverse events should be followed up until they have resolved or stabilized and 
proper documentation of the follow up must be provided, i.e. site call log. The sponsor 
must be advised of all grade 3 or 4 adverse events within one week of their identification, 
and of all serious adverse events within 24 hours of identification. Subjects will be 
followed up until the adverse event resolves or stabilizes. 
 
9.5 Defining, Grading and Reporting Adverse Events 
9.5.1 
Adverse Events 
All adverse events, 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 adverse event page(s) of the 
eCRF.  
 
For all adverse events, the Investigator must obtain adequate information to 
determine the cause and outcome of the adverse event, and to assess whether it 
meets the criteria for classification as a serious adverse event 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 adverse event, after the date of therapy discontinuation, is 
required until the adverse event 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. 
 

 
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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 adverse event, since it will be classified as a treatment 
failure. Pregnancy will not be considered to be an adverse event, but will be 
collected separately. However if the resultant child has a birth defect, this will be 
considered to be an SAE. 
 
Throughout the study, the Investigator must record all adverse events on the 
eCRF adverse event pages, regardless of the severity or relationship to study 
medication or procedure. The Investigator should treat subjects with adverse 
events appropriately and observe them at suitable intervals until the events resolve 
or stabilize. 
 
Adverse events can be discovered by observing the patient, questioning the 
patient objectively and/or receiving an unsolicited complaint from the patient. 
 
A subject’s AE’s will be collected from the start of the study medication until the 
subject’s last study visit. AE’s 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 adverse events 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: 
 
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. 
 
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. 
 
1. Inpatient hospitalization or prolongation of existing hospitalization. 
 
2. Persistent or significant disability/incapacity. 
 
3. Congenital anomaly/birth defect. 

 
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4. Spontaneous abortion or death of the infant within 1 month of birth. 
 
5. An event that required intervention to prevent permanent impairment or 
damage.  
 
6. 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.  However if the resultant child has a birth defect, this 
will be considered to be an SAE. (See section 9.5.5.) 
 
SAEs will be collected from the time of randomization until 28 days after 
completion of the trial or 28 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 a serious 
adverse event 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 adverse 
events occurring in study participants. To do this, the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 
grading system will be used in adverse event reporting. The purpose of using the 
CTCAE system is to provide a standard language to describe toxicities, to 
facilitate tabulation and analysis of the data, and to facilitate the assessment of the 
clinical significance of all adverse events. Adverse events should be recorded and 
graded 1 to 5 according to the CTCAE grades provided below: 
 
 
Grade 1 = Mild adverse event 
 
Grade 2 = Moderate adverse event 
 
Grade 3 = Severe and undesirable adverse event 
 
Grade 4 = Life-threatening or disabling adverse event 
 
Grade 5 = Death 

 
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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 Exposure In Utero 
(EIU) eCRF within 24 hours of awareness of the pregnancy. This must be done 
irrespective of whether an adverse event 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 Exposure in Utero Form. The 
reason(s) for an induced abortion should be specified. An EIU report is not 
created when an ectopic pregnancy report is received since this pregnancy is not 
usually viable. Rather, an SAE case is created with the event of ectopic 
pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as 
a serious adverse event (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 serious adverse 
events. 
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 an Exposure In Utero 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 serious 
adverse events follows:  
•    “Spontaneous abortion” includes miscarriage and missed abortion. 
•     All neonatal deaths that occur within 1 month of birth should be reported, 
without regard to causality, as serious adverse events. 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. 
 

 
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9.5.6 Relationship to Study Therapy 
The relationship between an adverse event 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. Code 1 is classified as unrelated and Codes 2-5 as related. (See Table 
11-1.) 
The Investigator’s determination of drug-relatedness (attribution) for each adverse 
event should be recorded in the source documentation.  
 
For additional information, please consult the Common Terminology Criteria for 
Adverse Events (CTCAE) v 4.03 and the Common Toxicity Criteria Document at 
the following URL: http://ctep.cancer.gov/reporting/ctc.html.  
 
 

 
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Table 11-1  
Attribution of Adverse Events 
 
ATTRIBUTION OF ADVERSE EVENTS 
“Unrelated” Category Code: 
Code 
Descriptor 
Definition 
1 
Unrelated 
The adverse event is clearly not related to the investigational 
agent(s). 
“Related” Category Codes: 
Code 
Descriptor 
Definition 
2 
Unlikely 
The adverse event is doubtfully related to the investigational 
agent(s). 
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). 
 
9.5.7 Abnormal Laboratory Findings 
The criteria for determining whether an abnormal objective test finding should be 
reported as an adverse event 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 adverse event by the Investigator or 
Sponsor. 
 
An abnormal test result, even if repeated, does not constitute an adverse event in 
the absence of any of the above conditions. Any abnormal test result that is 
determined to be an error does not require reporting as an adverse event. 

 
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Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 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 adverse events and all adverse 
events spontaneously reported by the trial subject. In addition, each trial subject 
will be questioned about adverse events 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 adverse event is to be classified by the Investigator as serious or non-
serious. This classification determines the reporting procedures to be followed. If 
a serious adverse event 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 serious adverse event 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 a serious adverse event occurs, the Generon Safety Officer and/or his/her agent 
are to be notified within 24 hours of awareness of the event by the Investigator. In 
particular, if the serious adverse event 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 adverse event information. This time frame also applies 
to additional new information (follow-up) on previously forwarded serious 
adverse event reports. 
 
In the rare event that the Investigator does not become aware of the occurrence of 
a serious adverse event 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 adverse 
event. 
 
For all serious adverse events, 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 to obtain specific 
follow-up information in an expedited fashion. This information may be more 
detailed than that captured on the adverse event electronic case report form. This 
will include a description of the adverse event 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 

 
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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 serious 
adverse events. An Investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product 
caused or contributed to an adverse event. 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 handled as “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 determines the adverse event 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 serious adverse event reporting requirements.  
 
All adverse events will be reported on the adverse event page(s) of the eCRF. It 
should be noted that the form for collection of serious adverse event information 
is not the same as the adverse event eCRF. Where the same data are collected, the 
forms must be completed in a consistent manner. For example, the same adverse 
event term should be used on both forms / eCRFs. Adverse events 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 serious adverse event 
information. 
 
Non-serious adverse events are to be reported on the adverse event page of the 
eCRFs, which are to be submitted to Generon as specified in the adverse event 
report submission procedure for this protocol.  
 
If a subject begins a new therapy, the adverse event-reporting period will end at 
the time that the new treatment is started. 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, 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. 
 

 
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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 patient 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 in days of grade 4 (severe) neutropenia (ANC < 0.5 x 109/L) for 
chemotherapy cycles 2, 3, and 4, and over all cycles.  
 
The duration in days of grade 2 (mild, ANC < 1.5 × 109/L) and 3 (moderate, ANC < 
1.0 × 109/L) neutropenia () for each chemotherapy cycle and over all cycles. 
 
The incidence rates of febrile neutropenia (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 
× 109/L) for each chemotherapy cycle. 
 
The incidence rates of grade 2, grade 3, and grade 4 neutropenia for all chemotherapy 
cycles. 
 
The time in days to ANC recovery post nadir for each chemotherapy cycle and over 
all cycles; recovery is defined as an ANC ≥ 2.0 × 109/L after the expected ANC nadir. 
 
The depth of the ANC nadir for each chemotherapy cycle and over all cycles.  
 
The incidence rates of infections for each chemotherapy cycle and over all cycles. 
 
The use of antibiotic and pain medications for each chemotherapy cycle and over all 
cycles. 
 
ECG endpoints: Change-from-baseline heart rate, PR, QRS and QTcF intervals. 
Categorical outliers and T-wave morphology changes on treatment. 
 
 
10.1.3 Safety Analysis 
Safety analysis will include number of subjects reporting AEs/SAEs as well as 
investigations such as standard lab tests (including hematology, blood chemistry 
and urinalysis), physical examination and vital sign measurements. 
 
10.2 Statistical Methods  
Efficacy analysis will be based on the Intent-To-Treat analysis set with the Per Protocol 
analysis set used for sensitivity analysis. The Safety analysis set will be used in safety 
analysis. 

 
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Categorical variables will be summarized as the number and percentage of subjects in each 
category. Continuous variables will be summarized using the mean, median, range and 
standard deviation for each endpoint listed in section 10.1. 
 
10.2.1 Efficacy Analysis 
10.2.2 Primary Efficacy Analysis 
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 Placebo in the 
first chemotherapy cycle. The primary endpoint will be the duration of severe 
neutropenia (ANC < 0.5 x 109/L) observed in chemotherapy cycle 1.  
 
10.2.3 Secondary Efficacy Analysis 
Similar to the primary analysis, all secondary analyses will be reported within 
each chemotherapy regimen. 
 
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.  
 
Duration of grade 3 (Moderate) neutropenia for all chemotherapy cycles 
The duration comparisons of grade 3 neutropenia (this includes by default grade 4 
or severe neutropenia) between groups of F-627 and Placebo within 12 days 
chemotherapy treatment  for Cycle 1 will be described by a 95% CI of the 
difference between the treatments. The 95% CI will be calculated in same manner 
as the primary efficacy analysis. The duration of grade 3 neutropenia within 12 
days chemotherapy treatment for cycles 2, 3 and 4 will be summarized. 
 
Duration of grade 2 (Mild) neutropenia for all chemotherapy cycles 
The duration comparisons of grade 2 neutropenia (this includes by default grade 3 
and grade 4 neutropenia) between groups of F-627 and Placebo within 12 days 
chemotherapy treatment  for Cycle 1 will be described by a 95% CI of the 
difference between the treatments. The 95% CI will be calculated in same manner 
as the primary efficacy analysis. The duration of grade 2 neutropenia within 12 
days chemotherapy treatment for cycles 2, 3 and 4 will be summarized.   
 
ANC profiles 

 
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For comparing the effectiveness of the F-627 dose to Placebo, 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 for all groups.  
 
Incidence rates of grade 2 (Mild), grade 3 (Moderate), and 4 (severe) 
neutropenia for all chemotherapy cycles  
Definitions of grade 2, grade 3, and grade 4 neutropenia are in section 10.1.2.  
The frequency and percent of grade 2 to 4, grade 3 to 4 and grade 4 neutropenia 
for each chemotherapy cycle will be summarized. The incidence difference of 
neutropenia between F-627 and Placebo will be tested by Fisher’s Exact Test for 
Cycle 1. 
                                
Time to ANC recovery 
The mean time difference of ANC recovery to ≥ 2 × 109/L from ANC nadir 
between F-627 and Placebo in Cycle 1 will also be compared with a 95% CI.  
                                
Febrile neutropenia 
The frequency and incidence rate of febrile neutropenia (defined in section 
10.1.2) will be summarized for cycle. The incidence difference of febrile 
neutropenia between F-627 and Placebo will be tested by Fisher’s Exact Test for 
Cycle 1.  
 
Depth of ANC nadir 
The lowest ANC values within 12 days chemotherapy treatment will be 
summarized for each cycle. A two-sided 95% Wald CI of the ratio of ANC nadir 
between F-627 and Placebo will calculated by Fisher’s Exact Test for Cycle 1.  
 
 
10.2.4 Safety Analysis 
Safety will be assessed on the number of subjects reporting an AE/SAE, and on 
physical examination, vital sign measurement and clinical laboratory test results.  
 
Adverse events will be tabulated by system organ class and preferred term 
according to a standardized coding thesaurus (MedDRA). The severity of AE’s 
will be classified using the NCI-CTCAE toxicity scale as detailed in section 
11.5.4.  AE summaries will be provided in separate tables for serious AEs, 
treatment-related AEs, and AEs leading to study discontinuation. AEs will also be 
summarized by maximum severity.  
 

 
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Concomitant medications including those ongoing at baseline will be tabulated by 
drug category and preferred term. 
 
Physical examination findings will be summarized within medical history or AE 
summary analyses, where applicable. Descriptive statistics for vital sign 
measurements, by treatment and time (after dose), will also be provided. 
Hematological, blood chemistry and urinalysis data will be graded according to 
NCI-CTCAE severity grade. Shift tables from baseline to post-baseline visits will 
be presented for clinical laboratory measurements (serum chemistry, hematology, 
and urinalysis). 
 
A 12 lead ECG will be conducted at baseline, prior to each administration of 
study drug dose, and at the end of study. PR and QRS interval data with a separate 
QT study report and descriptive waveform morphology changes; review of ECGs 
from a particular subject should be performed by a single reader; pre-specify the 
lead for interval measurements.  
 
 
10.2.5 Sample Size Calculation 
Assuming an expected difference in the duration of severe neutropenia for F-627 
as compared to Placebo of 2.0 days, with a common standard deviation of 3 days, 
this Phase III global clinical study will randomize approximately 120 subjects in a 
2:1 ratio of F-627 and Placebo, respectively. The dropout rate for the trial is 
assumed to be 10%. Under these assumptions, enrollment of 80 subjects for the F-
627 arm and 40 subjects for the Placebo arm for Cycle 1 would be required to 
realize 90% power 
 
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 IRB/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. 
 

 
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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, the 
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 Statistical Analysis Plan (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. 
 
10.6.2 Intent to Treat Analysis Set  
All randomized subjects will be included in the Intent-to-Treat (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 planned 
randomized treatment. The ITT analysis set will be used as the primary analysis 
set in the efficacy analyses.  
 
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 included in the Per Protocol (PP) analysis set. Major 
protocol deviations and subjects 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 supportive analysis in the efficacy analyses. 
 
 
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. 
 

 
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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. 
 
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, International Conference on 
Harmonization Good Clinical Practice guidelines, and applicable local regulatory 
requirements and laws. 
 

 
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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 4.3. 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. 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. 
 

 
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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. 
 
 
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 

 
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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. 
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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 
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6.  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, 
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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. 
8.  Glaspy,J.A., and Golde,D.W. 1992. Granulocyte colony-stimulating factor (G-CSF): 
preclinical and clinical studies. Semin. Oncol. 19:386-394. 
9.  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. 
10.  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. 
11.  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. 
12.   Neupogen (filgrastim) prescribing information. http://www neupogen.com/pi.html. 
13.   Neulasta Product information. www.neulasta.com/patient/neulasta-product-information html. 

 
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14.  Lyman,G.H. 2005. Pegfilgrastim: a granulocyte colony-stimulating factor with 
sustained duration of action. Expert. Opin. Biol. Ther. 5:1635-1646. 
15.  Molineux,G. 2004. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, 
Neulasta). Curr. Pharm. Des. 10:1235-1244. 
16.  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. 
17.  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. 8:195-200. 
18.  A del Giglio, A Eniu, D Ganea-Motan, E Topuzov and H Lubenau. 2008. XM02 is 
superior to placebo and equivalent to NeupogenTM in reducing the duration of severe 
neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients 
receiving docetaxel/doxorubicin chemotherapy. BMC Cancer. 8:332  
 
 
 

 
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18 APPENDICES  
 
18.1 Trial Procedures and Activities 
Pregnancy tests will be performed at screening (serum). 
 
Initial Screen (within 2 weeks 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 (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  
• 
Urinalysis  
• 
Centrally read 12-lead ECG  
• 
Chest X-Ray  
• 
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 F-627 antibodies assay. 
• 
Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, 
Bicarbonate, Calcium, Phosphorus, Glucose, Bilirubin, ALT, AST, Alkaline 
Phosphatase, GGT, LDH) 
• 
Centrally read 12-lead ECG (cycles 2-4) 
• 
Collection of adverse events 

 
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• 
Concomitant medications  
 
Administration of chemotherapy should be upon completion of the above tests. 
Randomization should occur after chemotherapy has been administered. 
 
• 
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, smear sample 
• 
Collection of adverse events 
• 
Concomitant medications 
• 
Chemotherapy Cycle 1 ONLY: Administration of F-627 20mg fixed dose PFS or 
placebo  (performed upon test completion) 
• 
Chemotherapy Cycles 2-4: Administration of F-627 20mg fixed dose PFS 
 
*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, smear sample 
• Serum collection for F-627 antibody test (only on day 12 (+1 day allowed) for each 
chemotherapy cycle) 
• Collection of adverse events 
• Concomitant medications 
 
• Final day of daily CBC is dependent on 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.  
 
 
For Chemotherapy Cycles 2-4, Cycle Days 3-21*(corresponds to study days 3-84):  
 
• Body temperature 
• CBC with Differentials, local and central lab sample, smear sample 
• Collection of adverse events 

 
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• Concomitant medications 
 
* CBC is dependent on individual subject’s ANC levels; tests to occur (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 × 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 > 0.5 × 109/L.   
 
End of Study (3 weeks after last dose; corresponds to study day 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 F-627 antibody test 
• Urinalysis  
• Centrally read 12-lead ECG  
• Chest X-Ray  
• Collection of adverse events 
• Concomitant medications  
 
 
 

 
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18.3 Central Lab Locations 
 
Please refer to the study central lab manual for the local shipment address for clinical study 
samples. 
 
 
 
  

 
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18.4  Definition of Abbreviations and Definitions of Terms 
 
Glossary of Abbreviations and Terms 
% percent 
<, ≤ less than, less than or equal to 
>, ≥ greater than, greater than or equal to 
μg microgram 
μl microliter 
AC Active controlled 
AE Adverse event 
ALP Alkaline Phosphatase 
ALT Alanine aminotransferase 
ANC Absolute neutrophil counts 
AST  Aspartate aminotransferase 
ATCC American Tissue Culture Collection 
AUC area under the plasma concentration vs. time 
curve 
BW Body weight 
BUN Blood Urea Nitrogen 
ºC Degrees Centigrade (Celsius) 
Cmax  Concentration Maximum 
CBC Complete Blood Count 
CFR Code of Federal Regulations 
cGMP Current Good Manufacturing Practice 
CHO Chinese Hamster Ovary 
CI Confidence interval 
CL/F Oral Clearance 
CO Comparative and open 
eCRF Electronic Case Report Form 
CRO Contract Research Organization 
CTCAE National Cancer Institute Common 
Terminology Criteria for Adverse Events 
dL decaliter 
DMF Drug Master File 
ECG/EKG Electrocardiogram 

 
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ECOG Eastern Cooperative Oncology Group 
EIU Exposure in Utero 
ºF Degrees Fahrenheit 
FDA Food and Drug Administration 
g Grams 
GCP Good Clinical Practice 
GCSF  Granulocyte colony-stimulating factor 
GMP Good Manufacturing Practices 
h hour 
Hgb Hemoglobin 
HIV Human Immunodeficiency Virus 
ICH International Conference on Harmonization 
IEC Independent Ethics Committee 
Ig Immunoglobulin 
IND Investigational New Drug 
IRB Institutional Review Board 
ITT Intent-to-Treat 
i.v. (IV) Intravenous 
IWRS Interactive Web-based Response System 
kg kilogram 
L Liter 
LOCF Last Observation Carried Forward 
MedDRA Medical Dictionary for Regulatory Activities 
mg milligram 
mL milliliter 
mm millimeter 
MRSD Maximum Recommended Starting Dose 
N Number 
NA Not available 
NCI National Cancer Institute 
ng nanogram 
NOAEL No Observed Adverse Effect Level 
PK Pharmacokinetics 
Plt Platelet 

 
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PP Per Protocol 
QC Quality Control 
rhG-CSF Recombinant human granulocyte colony 
stimulating factor 
SAE Serious Adverse Event 
SAP Statistical Analysis Plan 
sc Subcutaneous 
SD Standard Deviation 
SEM Standard Error of the Mean 
SFDA State Food and Drug Administration 
T ½ abs Absorption half life (of a drug) 
TEAE Treatment Emergent Adverse Event 
Tmax Maximum concentration (of a drug in 
bloodstream) 
ULN Upper Limit of Normal 
WBC White Blood Cell 
WFSI Water for Subcutaneous Injection