Conditions: Breast Cancer Neutropenia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 122
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind and placebo controlled phase 3 study to evaluate the efficacy and safety of F-627 in women with stage II-IV breast cancer receiving chemotherapy treatment.

Detailed description:
This is a randomized, multi-center, single dose, double-blind, placebo controlled phase III study of the efficacy and safety of once-per-cycle of F-627 in women with stage II-IV breast cancer who are receiving myelotoxic TA chemotherapy treatment (Taxotere (docetaxel) + Adriamycin(doxorubicin)). F-627 is designed to treat neutropenia, an abnormally low number of neutrophils (a type of white blood cell) in the blood. Neutropenia is often seen in cancer patients receiving myelotoxic chemotherapy.

The primary objective of this study is to evaluate the efficacy and safety of single fixed dose of F-627 in breast cancer patients experiencing myelotoxic chemotherapy in comparison to placebo. F-627 or placebo is to be administered subcutaneously 24 hours after chemotherapy in each 21-day cycle of chemotherapy treatment (up to 4 cycles). Patients randomized to placebo arm will receive F-627 except in cycle 1. The primary endpoint will be the duration of grade 4 (severe) neutropenia - the number of days in which the patient has had an absolute neutrophil count (ANC \< 0.5 x 10\^9/L) observed in chemotherapy cycle 1.

Arms:
arm 1: F-627, 20 mg fixed dose pre-filled syringe, dosed Day 2 of each of 4 chemotherapy cycles. arm 2: Placebo, 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.

Interventions: intervention 1: F-627 intervention 2: Placebo
Intervention descriptions: intervention 1: F-627 subcutaneous injection on Day 2 of TA chemotherapy cycles. TA chemotherapy treatments are part of standard-of-care and not the study intervention 2: Placebo subcutaneous injection on Day 2 of the first TA chemotherapy cycle. TA chemotherapy treatments are part of standard-of-care and not the study.

Protocol document:
SAP_002.pdf: 
 
 
Statistical Analysis Plan 
Protocol Number: GC-627-04 
 
 
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STATISTICAL ANALYSIS PLAN 
 
 
 
Trial Sponsor: 
Generon (Shanghai) Corporation Ltd. 
Protocol Number: 
GC-627-04 
IND Number: 
 
Investigational Drug: 
F-627 
Indication: 
Myelotoxic Chemotherapy Induced Neutropenia 
Dosage Form/Strength: F-627, 20 mg fixed dose 
 
Protocol Title: A Phase III, Randomized, Multi-Centre, Double-Blind, Placebo Controlled Clinical 
Trial of F-627 in Women with Breast Cancer Receiving Myelotoxic Chemotherapy 
 
 
Last Revision Date: 
14 December 2017 
Version: 
1.0  
Final Sign-off Date: 
 
Archive Date: 
 
 




 
 
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CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL 
Revision 
Date** 
Section(s)M
odified 
Brief Description of Revision(s) or 
Reason(s) for Revision 
Modifications Reviewed and 
Approved by* 
Sponsor, Everest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   Provide person’s initial and last name. 
** Update the Last Revision Dates on the cover page and the document header. 
 


 
 
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TABLE OF CONTENTS 
APPROVAL SIGNATURES ........................................................................................................................ 2 
GLOSSARY OF ABBREVIATIONS .......................................................................................................... 6 
1. 
INTRODUCTION ................................................................................................................................ 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................ 8 
2.1 
Primary Efficacy Objective ........................................................................................................ 8 
2.2 
Primary Efficacy Endpoint ......................................................................................................... 8 
2.3 
Secondary Efficacy Endpoints .................................................................................................... 8 
2.4 
Safety Objective.......................................................................................................................... 9 
2.5 
 ............................................................................................................... 9 
3. 
STUDY DESIGN .................................................................................................................................. 9 
3.1 
Study Design ............................................................................................................................... 9 
3.2 
Schedule of Assessments .......................................................................................................... 11 
3.3 
Randomization .......................................................................................................................... 12 
3.4 
Hypothesis Testing ................................................................................................................... 12 
3.5 
Interim Analysis ....................................................................................................................... 12 
3.6 
Sample Size .............................................................................................................................. 13 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE .................................................................. 13 
5. 
ANALYSIS POPULATIONS ............................................................................................................. 13 
5.1 
Intent-to-Treatment (ITT) Population ....................................................................................... 13 
5.2 
Per Protocol (PP) Population .................................................................................................... 13 
5.3 
Safety Population ...................................................................................................................... 13 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES ................................................................. 13 
6.1 
Demographic and Baseline Characteristics .............................................................................. 14 
6.1.1 
Demographics and Baseline Characteristics .............................................................. 14 
6.1.2 
Medical and Surgery History, Prior Cancer Systemic Therapy and Cancer 
Radiotherapy .............................................................................................................. 14 
6.1.3 
Physical Examination ................................................................................................. 15 
6.1.4 
Prior and Concomitant Medication ............................................................................ 15 
6.1.5 
Myelotoxic Chemotherapy Administration ................................................................ 15 
6.2 
Efficacy ..................................................................................................................................... 16 
6.2.1 
Study Day and Relative Study Day ............................................................................ 16 
6.2.2 
Primary Efficacy Variables ........................................................................................ 16 
6.2.3 
Key Secondary Efficacy Variables ............................................................................. 16 
6.2.4 
Other Secondary Efficacy Variables .......................................................................... 17 
6.3 
Exploratory Variables ............................................................................................................... 19 


 
 
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6.4 
Safety ........................................................................................................................................ 19 
6.4.1 
Safety Baseline and Study Day .................................................................................. 19 
6.4.2 
Extent of Exposure to Study Medication.................................................................... 19 
6.4.3 
Adverse Events ........................................................................................................... 20 
6.4.4 
Laboratory Data .......................................................................................................... 21 
6.4.5 
Vital Signs .................................................................................................................. 22 
6.4.6 
Electrocardiogram ...................................................................................................... 22 
6.4.7 
Other Safety Assessments .......................................................................................... 23 
7. 
STATISTICAL ANALYSIS ............................................................................................................... 23 
7.1 
General Data Handling Rules and Definitions ......................................................................... 23 
7.1.1 
Missing Data and Imputation ..................................................................................... 23 
7.2 
Subject Disposition ................................................................................................................... 23 
7.3 
Demographic and Baseline Characteristics .............................................................................. 24 
7.4 
Efficacy Analyses ..................................................................................................................... 24 
7.4.1 
Primary Efficacy ........................................................................................................ 25 
7.4.1.1 
Prevention and Treatment of Missing Data ............................................... 25 
7.4.1.2 
Multiple Imputations for Primary Analysis ............................................... 26 
7.4.1.3 
Sensitivity Analyses ................................................................................... 27 
7.4.2 
Key Secondary Efficacy ............................................................................................. 32 
7.4.2.1 
Missing Data Handling for Secondary Efficacy Endpoints ....................... 33 
7.4.2.2 
Sensitivity Analyses ................................................................................... 34 
7.4.3 
Other Secondary Efficacy .......................................................................................... 34 
7.5 
Safety Analyses ........................................................................................................................ 35 
7.5.1 
Extent of Exposure to Study Medication.................................................................... 36 
7.5.2 
Adverse Events ........................................................................................................... 36 
7.5.2.1 
Incidence of Adverse Events ..................................................................... 36 
7.5.3 
Laboratory Data .......................................................................................................... 37 
7.5.4 
Vital Signs .................................................................................................................. 37 
7.5.5 
Electrocardiogram ...................................................................................................... 37 
7.5.6 
Other Safety Assessments .......................................................................................... 37 
8. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................. 37 
9. 
STATISTICAL SOFTWARE ............................................................................................................. 38 
10. REFERENCES .................................................................................................................................... 38 
APPENDIX 1 
 DATA HANDLING RULES .................................................................................... 39 
APPENDIX 2 
 SAS CODE FOR STATISTICAL ANALYSES ....................................................... 39 
APPENDIX 3 
 MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) ..................................... 42 
APPENDIX 4  
 REFERENCE RANGES FOR LABORATORY ABNORMALITIES ..................... 43 
 
 


 
 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
ANC 
Absolute neutrophil counts 
Cmax  
Concentration Maximum  
CBC 
Complete Blood Count 
CI 
Confidence interval 
CNS  
Central nervous system 
eCRF 
Electronic Case Report Form 
CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EU 
European Union  
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IWRS 
Interactive Web-based Response System 
MAR  
Missing at random 
MCMC 
Monte-Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MNAR 
Missing not at random 
NCI 
National Cancer Institute 
PFS 
Prefilled syringe  
PK  
Pharmacokinetics  


 
 
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Abbreviation 
Term 
PMM 
Pattern mixture model 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
WBC 
White Blood Cell 
 


 
 
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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and analysis 
of data collected within the scope of Generon (Shanghai) Corporation Ltd. protocol GC-627-04, Protocol 
Amendment 1.0 dated May 07, 2017. The purpose of this plan is to provide general guidelines from 
which the analysis will proceed. Nevertheless, deviations from these guidelines must be substantiated by a 
sound statistical rationale. 
The SAP should be read in conjunction with the study protocol and the Case Report Forms (CRFs). This 
version of the SAP has been developed using the final version of the protocol mentioned above and the 
study CRFs.  
This is a phase III, randomized, multi-center, double-blind, placebo controlled clinical trial of F-627 in 
women with breast cancer receiving myelotoxic chemotherapy to evaluate the efficacy and safety of F-
627 given as a single fixed dose pre-filled syringe in comparison to Placebo. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Efficacy Objective 
The primary objective of this study is to evaluate the efficacy and safety of F-627 given as a single fixed 
dose (20 mg) pre-filled syringe (PFS) as compared to Placebo in the first chemotherapy cycle.  
2.2 
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. 
2.3 
Secondary Efficacy Endpoints 
For all secondary analyses, the endpoints will be measured for each cycle as well as over all cycles.  
• 
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 x 109/L) for each 
chemotherapy cycle and over all cycles. 
• 
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 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. 




 
 
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If a subject’s ANC is < 0.5 × 109/L for more than 6 consecutive 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.   
ANC Assessment for Chemotherapy Cycle 1: 
Subjects are required to return 24 hours after chemotherapy administration for study drug dosing. 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. 
ANC Assessment for 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. 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. 
 
 
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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3.3 
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. 
3.4 
Hypothesis Testing 
Primary Efficacy Analysis 
For the primary efficacy analysis, superiority of F-627 vs. Placebo in the first chemotherapy cycle will be 
tested using the following null and alternative hypotheses to compare the duration of severe neutropenia 
between F-627 vs. Placebo: 
H0: µPlacebo-µF-627  = 0 day  vs. Ha:  µPlacebo-µF-627  ≠ 0 day 
This two-sided hypothesis test will use an α of 0.05 for the comparison. Superiority will be claimed if the 
lower bound of the 95% CI is > 0. 
 
Secondary Efficacy Analysis 
If the primary analysis infers F-627 is superior compared to Placebo, then a subset of key secondary 
endpoints listed below will be tested using a fallback method in order to retain the type I error rate 
. Similar to fixed sequence procedure, the fallback method tests hierarchically ordered hypotheses in 
sequence but splits the level of α between the hypotheses. Unlike fixed sequence procedure, the fallback 
procedure tests all hypotheses in the pre-specified sequence even if the initial hypotheses are not rejected. 
As a result, the fallback method for ordered hypotheses provides the opportunity to test an endpoint later 
in the sequence and gains additional power by allocating a higher α level to a hypothesis if the hypothesis 
earlier in the sequence is rejected. 10,11 The sequence of secondary endpoints and their allocated α is listed 
below: 
1. The incidence rate of febrile neutropenia for chemotherapy cycle 1. α=0.04. 
2. The incidence rate of infection for chemotherapy cycle 1. α=0.005. 
3. The duration in days of grade 3 neutropenia for chemotherapy cycle 1. α=0.001. 
4. The duration in days of grade 2 neutropenia for chemotherapy cycle 1. α=0.001. 
5. The incidence rate of use of antibiotic for chemotherapy cycle 1. α=0.001. 
6. The incidence rate of use of pain medications for chemotherapy cycle 1. α=0.001. 
7. The incidence rate of grade 4 neutropenia for chemotherapy cycle 1. α=0.001. 
 
3.5 
Interim Analysis 
No interim analysis is planned for this study.   


 
 
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3.6 
Sample Size 
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, enrolment 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. 
4. DATA AND ANALYTICAL QUALITY ASSURANCE 
The overall quality assurance procedures for the study data, statistical programming and analyses are 
described in the Everest’s Standard Operating Procedures. Detailed statistical and programming quality 
control and quality assurance procedures are documented in the Statistical Analysis and Programming 
QC/QA Plan.  
The study endpoints and analytic approaches are both prospectively defined and documented in the 
protocol and in this SAP finalized prior to the database lock and data analysis. 
5. ANALYSIS POPULATIONS 
5.1 
Intent-to-Treatment (ITT) Population 
All randomized subjects will be included in the 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. 
 
5.2 
Per Protocol (PP) Population 
All subjects from the ITT Analysis Set who received study treatment, who are eligible and compliant and 
without major protocol deviations during the first cycle of treatment will be included in the PP Analysis 
Set. Major protocol deviations and subjects (or data) excluded from the PP Analysis Set will be defined 
by the Sponsor in a blinded manner prior to database lock. The PP Analysis Set will be used as the for 
sensitivity analysis of all endpoints. Major protocol deviations include, but are not limited to, receiving 
incorrect treatment, or non-compliance to ANC collection in the first 12 days of cycle 1 that may affect 
the primary endpoint.  
5.3 
Safety Population 
All enrolled subjects receiving F-627 or Placebo treatment will be included in the Safety Analysis Set, 
which will be used for all safety analyses. The data in the Safety Analysis Set will be analyzed according 
to the treatment received. 
6. SPECIFICATION OF ENDPOINTS AND VARIABLES 
Several analytic variables must be derived from the data as it was collected. This section describes the 
variables collected, as well as how they will be modified for inclusion in the analyses. 


 
 
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6.1 
Demographic and Baseline Characteristics 
6.1.1 
Demographics and Baseline Characteristics 
Demographic parameters collected include: age, sex, race, ethnicity, country/region, and reproductive 
status. Baseline characteristics, including weight (kg) and height (cm), BMI, BSA, days from diagnosis, 
screening ECOG performance score and stage of cancer (II to IV) will also be summarized. 
 
Age, body mass index (BMI), body surface area (BSA) and days since diagnosis will be computed as: 
Description 
Data Handling Rule 
Age (years) 
Age = integer((date of informed consent-date of birth)/365.25)   
BMI 
BMI = Weight (kg) / [Height (cm)/100]2 
BSA 
BSA =( [Height (cm) x Weight (kg) ]/ 3600 )1/2 
Days since diagnosis 
Days since diagnosis = Date of randomization – Date of 
diagnosis 
 
6.1.2 
Medical and Surgery History, Prior Cancer Systemic Therapy and Cancer 
Radiotherapy 
Medical and surgical history, prior cancer systemic therapy and prior cancer radiotherapy will be 
collected. 
General medical and surgical history will include a description of the diagnosis or procedures, start and 
end date, and if the condition is still ongoing. 
Prior cancer systemic therapy will be categorized by therapy code:  
• 
Chemo/anthracycline 
• 
Chemo/non-anthracycline 
• 
Hormonal 
• 
Biologic 
• 
Myeloablative therapy 
• 
Bone marrow or stem cell transplant 
• 
Other 
Agent name, reason for stopping and first/last dose dates will be recorded on the eCRF. 
Prior cancer radiotherapy will be categorized by radiation site: 
• 
Right breast 
• 
Left breast 
• 
Bone 
• 
Liver 
• 
Lung 
• 
Lymph nodes 
• 
Abdomen 


 
 
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• 
Mediastinum 
• 
Central nervous system (CNS) 
• 
Pelvis 
• 
Skin/Soft tissue 
• 
Other 
Radiation site description and last dose date will be collected on the eCRF. 
6.1.3 
Physical Examination 
A physical examination will be performed at screening and at each clinical visit as presented in the 
schedule of assessment (Table 1). Any change from baseline will be evaluated and assessed by the 
Investigator. An abbreviated physical exam may be completed at any visit as deemed appropriate by 
medical staff. Results of such abbreviated physical exams will be collected on the eCRFs. 
6.1.4 
Prior and Concomitant Medication 
Prior and concomitant medications will be recorded at screening and during the study. Prior medication is 
defined as any medication taken before the first dose of chemotherapy. Concomitant medication is 
defined as any medication taken during the study between the date of the first dose of chemotherapy and 
the date of subject discharge from the study three weeks after last dose of study drug or at the time of 
early termination. Any medication that started after the subject discharge from the study, three weeks 
after last dose of study drug, or at the time after early termination will not be considered a concomitant 
medication. 
Any medication which cannot be identified as prior or concomitant will be considered as being in both of 
the categories that are possible from the available information. 
All prescription and over-the-counter (OTC) medications, including herbal supplements, taken by the 
subject within 3 months prior to the Screening visit and throughout the study will be recorded on the Prior 
and Concomitant Medications form.  
Any additions, deletions, or changes in the dose of these medications while on study should be recorded. 
Any current ongoing medications, including OTC drugs and herbal supplements, will be allowed 
provided they are not prohibited by the protocol and are approved by the Investigator. 
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 rescue medication should be documented on the 
concomitant medication eCRF and the subject’s ANC level should be closely monitored until recovered. 
Medications will be coded using latest version of the World Health Organization Drug Dictionary (WHO-
DD) available. 
6.1.5 
Myelotoxic Chemotherapy Administration 
For each of the four cycles, the following chemotherapy administration details will be collected on Cycle 
Day 1, for each of the two agents (docetaxel and doxorubicin): 


 
 
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• 
Infusion date and start/end time  
• 
Dose level: 
• 
docetaxel: 75 mg/m²  
• 
doxorubicin: 60 mg/m²  
• 
Planned Dose (mg) 
• 
Total Volume Prepared (mL) 
• 
Total Volume Infused (mL) 
• 
The Actual dose given (mg) can be calculated as (Planned Dose x Total Volume Infused) / Total 
Volume Prepared. 
6.2 
Efficacy 
The intent-to-treat (ITT) and per-protocol (PP) populations will be used for the efficacy analyses. 
Efficacy analysis will be primarily based on the ITT population and the PP analysis population will be 
used for sensitivity analysis. 
There will be no imputation of the missing primary endpoint data in the PP analysis. Handling of missing 
values is covered in section 7.1.1. 
6.2.1 
Study Day and Relative Study Day 
The date of the first dose of chemotherapy in Cycle 1 represents Study Day 1. 
Study day will be computed from cycle 1, day 1 as:   
Study day = (date of interest) – (date of Study Day 1) + 1 
For each cycle, the date of the first dose of chemotherapy represents Relative Study Day 1. 
Relative study day will be based on each cycle as: 
Relative study day = (date of interest) – (date of Relative Study Day 1) + 1 
6.2.2 
Primary Efficacy Variables 
The duration of grade 4 (severe) neutropenia is defined as the number of days in which the subject has 
had an ANC < 0.5 × 109/L during cycle 1. 
Duration = (Date of last ANC < 0.5 × 109/L within cycle) – (Date of first ANC <0.5 × 109/L within cycle) 
+ 1 
If subject does not experience neutropenia during the first 12 days of cycle 1, Duration = 0 days. 
6.2.3 
Key Secondary Efficacy Variables 
For all key secondary analyses, the F-627 group will be compared to the Placebo group. 
The secondary endpoints are: 
• 
The incidence rate of Febrile neutropenia for chemotherapy cycle 1. 
Febrile neutropenia is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of 
>38.0°C (100.4°F) sustained for >1 hour and ANC <0.5 x 109/L. Investigators are to report 
occurrences of febrile neutropenia as an AE. 


 
 
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Incident rate (%) = 100% × (Number of subjects with at least one incidence of febrile neutropenia 
/ Total number of subjects in the population) 
Febrile neutropenia will be based on AE reporting and MedDRA coding. If a subject has more 
than one incidence of febrile neutropenia, it will be counted only once when calculating the 
incidence of febrile neutropenia over all cycles. 
• 
The incidence rate of infection for chemotherapy cycle 1. 
Incident rate (%) = 100% × (Number of subjects with infection / Total number of subjects in the 
population) 
Infections will be based on AE reporting and MedDRA coding. If a subject has more than one 
incidence of infection, it will be counted only once. 
• 
Duration of grade 3 (Moderate) neutropenia for chemotherapy cycle 1. 
The duration of grade 3 (Moderate) neutropenia is defined as the number of days in which the 
subject has had an ANC < 1.0 × 109/L during cycle 1. 
• 
Duration of grade 2 (Mild) neutropenia for chemotherapy cycle 1. 
The duration of grade 2 (Mild) neutropenia is defined as the number of days in which the subject 
has had an ANC < 1.5 × 109/L during cycle 1. 
• 
The incidence rate of use of antibiotic medication for chemotherapy cycle 1. 
Incident rate (%) = 100% × (Number of subjects with at least one use of antibiotic medication / 
Total number of subjects in the population) 
Antibiotic medication will be based on concomitant medication reporting and WHO-DD coding. 
If a subject has more than one incidence of antibiotic use, it will be counted only once. 
• 
The incidence rate of use of pain medication for chemotherapy cycle 1. 
Incident rate (%) = 100% × (Number of subjects with at least one use of pain medication / Total 
number of subjects in the population) 
Pain medication will be based on concomitant medication reporting and WHO-DD coding. If a 
subject has more than one incidence of pain medication use, it will be counted only once. 
• 
Incidence rates of grade 4 (Severe) neutropenia for chemotherapy cycle 1. 
Incident rate (%) = 100% × (Number of subjects with at least one incidence of grade 4 
neutropenia / Total number of subjects in the population) 
 
Incidence of neutropenia will be based on ANC values. If a subject has more than one incidence 
of neutropenia, it will be counted only once. 
6.2.4 
Other Secondary Efficacy Variables 
• 
Duration of grade 2 (Mild), grade 3 (Moderate) and grade 4 (Severe) neutropenia for cycles 2–4 
and over all cycles. 


 
 
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The duration of grade 4 (severe) neutropenia is defined as the number of days in which the 
subject has had an ANC < 0.5 × 109/L during cycle 2, 3 and 4. 
Duration = (Date of last ANC < grade definition × 109/L within cycle) – (Date of first ANC < 
grade definition × 109/L within cycle) + 1 
The duration of grade 2 (Mild) neutropenia is defined as the number of days in which the subject 
has had an ANC < 1.5 × 109/L during the cycle. 
The duration of grade 3 (Moderate) neutropenia is defined as the number of days in which the 
subject has had an ANC < 1.0 × 109/L during the cycle. 
The duration of grade 4 (Moderate) neutropenia is defined as the number of days in which the 
subject has had an ANC < 0.5 × 109/L during the cycle. 
If subject does not experience neutropenia during the first 12 days of cycle 2, 3 and 4, Duration = 
0 days.  
The duration over all cycles is the average of available individual durations for Cycle 1 to 4.  
• 
The incidence rate of Febrile neutropenia for chemotherapy cycles 2, 3, 4 and over all cycles. 
The incidence of febrile neutropenia over all cycles is any incidences occurred in cycle 1 to cycle 
4. 
• 
The time in days to ANC recovery post nadir for each chemotherapy cycle and over all cycles; 
recovery defined as an ANC ≥2.0 × 109/L after the expected ANC nadir. 
Nadir is the lowest observed ANC value in the first 12 days of that cycle. In case there are more 
than one lowest ANC values within 12 days chemotherapy treatment, the first point will be used 
as nadir. 
If at nadir point, ANC < 2.0 × 109/L, then: 
 
ANC Recovery = (Date when ANC ≥ 2.0 × 109/L post nadir) – (Date of nadir in this cycle) + 1 
If ANC ≥ 2.0 × 109/L during the first 12 days of cycle, then ANC Recovery = 0 days. 
The time in days to ANC recovery post nadir over all cycles is the average of individual available 
time to ANC recovery for Cycle 1 to 4. 
• 
Depth of ANC nadir for each chemotherapy cycle and over all cycles. 
The depth of ANC nadir is the lowest ANC value within 12 days chemotherapy treatment in the 
cycle. 
The depth of ANC nadir over all cycles is the average of individual depth of ANC nadir for Cycle 
1 to 4. 
• 
The incidence rate of use of antibiotic medication for chemotherapy cycles 2, 3, 4 and over all 
cycles. 
• 
The incidence rate of use of pain medication for chemotherapy cycles 2, 3, 4 and over all cycles. 
• 
The incidence rate of infection for chemotherapy cycles 2, 3, 4 and over all cycles. 
• 
The incidence rate of grade 4 (severe) neutropenia for chemotherapy cycles 2, 3, 4 and over all 
cycles. 


 
 
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• 
The incidence rate of grade 2(mild), grade 3(moderate) neutropenia for chemotherapy cycles 1, 2, 
3, 4 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. 
6.3 
Exploratory Variables 
• 
Analysis of serum samples from cycles 2 to 4 to determine if the formation of antibodies to F-627 
are present and, if antibodies are present, to evaluate the biological effects. Antibodies of interest 
are the immunoglobulin (Ig) G and IgM antibodies. 
6.4 
Safety 
• 
Adverse event reporting. 
• 
Vital sign measurements. 
• 
Laboratory measurements. 
• 
ECG measurements. 
• 
Physical Examination. 
Standard safety parameters include hematology, blood chemistry and urinalysis parameters, vital signs, 
physical examination, and symptom/toxicity assessment. The National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03 will be used to grade potential AEs. 
Local blood samples maybe used to determine the status of a subject’s ANC level for local safety 
monitoring and evaluation. 
6.4.1 
Safety Baseline and Study Day  
The baseline of safety measures are the last measure before chemotherapy of Cycle 1. 
Study day will be computed from cycle 1, day 1 as:   
Study day = (Date of interest) – (Date of Cycle 1 Day 1) + 1 
For each cycle, the date of the first dose of chemotherapy represents Relative Study Day 1. 
Relative study day will be based on each cycle as: 
Relative study day = (date of interest) – (date of Relative Study Day 1) + 1 
 
6.4.2 
Extent of Exposure to Study Medication 
Extent of exposure to study drug (F-627 or Placebo) will be assessed using the following variables: 
Description 
Definition/ Data Handling Rule 
Number of Treatment 
Cycles 
Number of Chemotherapy cycle participated, regardless the 
completion status. 
Treatment duration 
Treatment duration (weeks) = (Date of last F-627/Placebo– Date 
of first F-627/Placebo + 1) / 7 


 
 
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Total F-627 Received 
(mg) 
The total dosage of F-627 received for both F-627/Placebo arm 
subjects. Arm 1 will received 20mg F-627 for each cycle; Arm 2 
will received 20mg F-627 each cycle for cycle 2,3 and 4. 
Dose infused (mg) can be calculated as (Planned Dose x Total 
Volume Infused) / Total Volume Prepared. 
Number of Incompleted 
Doses (Overall and for 
each cycle) 
Number of subjects administrated with study drug but did not 
complete all dose from the pre-filled syringe. 
 
6.4.3 
Adverse Events 
Adverse events (AEs) will be collected and coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Analysis of adverse events will be carried out on the safety population. 
A treatment-emergent adverse event (TEAE) is any adverse event that begins on or after first 
chemotherapy treatment or is a worsening of a pre-existing medical condition. Incidence of TEAE will be 
presented by treatment group. SAEs will be collected from the time of randomization until 30 days after 
completion of the trial or 30 days after premature withdrawal of a subject from the trial.  
The severity of each AE will be classified using the NCI-CTCAE toxicity scale as follows: 
• 
Grade 1 = Mild 
• 
Grade 2 = Moderate 
• 
Grade 3 = Severe and undesirable 
• 
Grade 4 = Life-threatening or disabling 
• 
Grade 5 = Death 
The relationship of each AE will be assessed by the investigator in one of the following categories: 
• 
Unrelated 
• 
Unlikely 
• 
Possible 
• 
Probable 
• 
Definite 
An AE will be considered “related” to study drug if the relationship is “unlikely”, “possible”, “probable” 
or “definite”. 
Serious adverse events (SAE) are defined as any adverse events occurring at any dose that suggests a 
significant hazard, contraindication, side effect, or precaution. SAEs will be collected from the time of 
randomization until 30 days after completion of the trial or 30 days after premature withdrawal of a 
subject from the trial. 
If the death of a subject is reported at any point during the study, the date of death, autopsy performed 
(yes/no), and any clarifying information should be collected. The event causing death will be reported as a 
SAE. 
Adverse Events Counting Rules: 


 
 
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1. In the analyses, a subject having the same event (AE preferred term) more than once during the study 
will be counted only once for that event type.  
2. A subject with more than one different adverse event in a particular system organ class (SOC) will be 
counted only once in the total of subjects experiencing adverse events in that particular SOC. 
3. If an event changes in intensity or in seriousness during the study, it will be counted only once with 
the worst grade and seriousness respectively. 
4. If the causal relationship to the study drug is assessed differently, it will be counted only once by 
considering the “Worst” documented degree of relationship. 
Missing values will be treated as missing except for relationship, grade and seriousness of an AE, at 
which occurrence a “worst case” approach will be taken. Thus, if relationship is missing the AE will be 
regarded as related to the study drug, if the grade is missing the grade of the AE will be regarded as 
severe (Grade 3), if seriousness is missing the AE will be regarded as an SAE. 
Events with Irregular Start Dates: All treatment-emergent adverse events will be included in the 
tabulations regardless the completeness of the onset dates. Partial dates may be imputed when 
appropriate, as discussed below. 
If a partial date is reported for the start of an adverse event, a complete date will be estimated by the 
following algorithm: 
1. Only the year is reported: If the subject started receiving study medication in the prior year, then 
January 1 will be used as the starting date of the event. If the subject started receiving study 
medication in the year reported, then the date of the first dose of study medication will be used as the 
start of the event.  
2. The month and year are reported: If the subject started receiving study medication prior to the month 
and year reported, then the first day of the month will be used as the starting date of the event. If the 
subject started receiving medication during the month and year reported, then the date of the first dose 
of study medication will be used as the start of the event.  
If a partial date is reported for the end of an adverse event and the adverse event is not continuing, a 
complete date will be estimated by the following algorithm:  
1. Only the year is reported: If the subject started receiving study medication in the prior year, then the 
date of final study contact with the subject will be used as the end of the adverse event. If the subject 
started receiving study medication in the year reported, the earlier of December 31 or the date of final 
study contact with the subject will be used as the end of the adverse event.  
2. The month and year are reported: The earlier of the last day of the month or the date of final contact 
with the subject will be used as the end of the adverse event.  
Before the database lock, uncoded events will be assigned the string “UNCODED” as the body system, 
and the verbatim term will be used as the preferred term, so they can be included in the summary tables. 
In the final dataset, all the adverse events should have been coded.  
6.4.4 
Laboratory Data 
Central lab results will be primarily used for statistical analysis to ensure consistent measurements 
throughout the duration of the clinical trial, however in case of missing central lab results and existence of 
local lab result for efficacy analysis, local lab results will be used in place of missing central lab.  
Conversion to the International System of Units 


 
 
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All laboratory data will be stored in the database with the units in which they are originally reported. 
Laboratory data in summary tables and subject data listings will be presented in the International System 
of Units (SI units). Laboratory data not reported in SI units will be converted to SI units before further 
processing or data analysis. 
Hematology and blood chemistry data will be graded according to NCI-CTCAE severity grade.  
Baseline laboratory parameters (blood chemistry, hematology, and urinalysis) are defined as the subject’s 
last assessment prior to Cycle 1 Day 1of the initiation of chemotherapy.  
Change in laboratory parameters post baseline can be computed as: 
Change from baseline = Current Value – Baseline Value 
Missing laboratory values will not be imputed for the safety analysis. In case of repeated measurements at 
a given visit, the latest value will be used for analysis.   
6.4.5 
Vital Signs 
Vital signs are collected at Screening, each cycle’s Relative Day 1 and Relative Day 2, and at end of 
study, and include the following parameters: 
• 
Height (cm) (Screening only) 
• 
Weight (kg) 
• 
Heart rate (beats per minute [BPM]) 
• 
Diastolic and systolic blood pressure (mmHg) 
Body temperature will be measured in the same schedule as CBC.   
Baseline and change from baseline are defined similarly as in Section 6.4.4.  
6.4.6 
Electrocardiogram 
Standard 12-lead ECG will be measured at screening, each cycle’s Relative Day 2, and at the end of 
study. The following parameters are included:  
• 
PR Interval 
• 
QRS Duration 
• 
QT Interval 
• 
RR Interval 
• 
Heart Rate 
• 
QTc Fridericia Interval 
• 
Cardiologist Interpretation  
• 
T and U wave assessment 
Reading and interpretation of the ECG will be performed centrally and provided to the investigator.   
 


 
 
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6.4.7 
Other Safety Assessments 
Other safety assessments include: 
• 
Serum pregnancy test  
• 
Physical examination 
Any clinically significant abnormalities from physical examination will be reported as medical history if 
observed at Screening, or as an AE if observed after randomization. 
7. STATISTICAL ANALYSIS 
7.1 
General Data Handling Rules and Definitions 
All subjects randomized will be accounted for in the statistical analysis and presentation of the trial 
results.  
All data collected on case report forms will be provided in listings, except data collected only for 
confirmation of study entry criteria and for study administrative purposes. If any randomized subject is 
found to not have valid documented informed consent, that subject’s data will be excluded from the 
report.  
Except where specified, all continuous variables will be summarized with descriptive statistics (the 
number of non-missing values, mean, standard deviation, median, minimum and maximum) and all 
categorical variables will be summarized with frequency counts and percentages, by treatment group. 
7.1.1 
Missing Data and Imputation 
The primary endpoint, duration of grade 4 neutropenia in cycle 1, is calculated based on the daily 
assessment of ANC values. Every effort will be made to minimize the number of missing ANC values. 
These include collecting ANC values from the local lab in case of missing central lab ANC values due to 
technical reasons and monitoring the progress of the trial with acceptable missing data rate. Missing ANC 
values will be imputed for the primary analysis using multiple imputation methods described in section 
7.4.1.1 and 7.4.1.2. 
The rate and pattern of missing data will be explored and summarized. Pattern mixture models (PMM) 
with delta adjustments will be used to evaluate the impact of the missing ANC values and the robustness 
of inferences as part of the sensitivity analyses, and are described in sections 7.4.1.3.3 and 7.4.1.3.4.  
Per-protocol (PP) analysis will also be performed on primary endpoint as part of sensitivity analyses. 
Missing data will be maintained as missing for PP analyses. Critical efficacy data and major protocol 
deviations will be reviewed in a blinded data review meeting prior to database lock to determine the 
subjects to be excluded from the PP analyses. The meeting minutes with detailed reasons for subject 
exclusion will be reviewed and approved by the sponsor before database lock and filed in the clinical 
study report (CSR) Appendices.     
Imputation and missing data handling for secondary endpoints will be dependent on the secondary 
endpoint, and are discussed in section 7.4.2.1.    
7.2 
Subject Disposition 
Disposition tables will be presented by treatment group and for all subjects.  


 
 
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The number and percentage of subjects who failed the screening, were randomized into the study, and 
completed each of the four chemotherapy cycles will be tabulated. The number and percentage of subjects 
included and excluded from the defined analysis populations and reasons for study discontinuation will 
also be summarized for each treatment group. Other disposition information, reasons for screen failure 
and study discontinuation details will be provided in individual subject data listings.  
Major protocol deviations, such as significant non-compliance or other serious unforeseen violations 
deemed to invalidate the data collected for the purpose of the study will lead to exclusion of the data from 
the Per Protocol (PP) analysis population for efficacy analysis. In case of minor protocol deviations, data 
will not be excluded from the efficacy analysis. The rating of protocol deviations as “minor” or “major” 
will be decided on the basis of a blinded review of the data before declaration of “clean file” and lock of 
database. 
All protocol major deviations will be presented in subject data listings.  
7.3 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics variables will be summarized by treatment and all data will be 
provided in listings. 
Continuous baseline parameters (such as age, height, weight, BMI, BSA) will be summarized 
descriptively. For categorical baseline and demographic parameters (such as country, reproductive status, 
ethnicity, stage of cancer) frequencies of subjects will be provided. 
Number and percentage of subjects with medical history (any and by category), systemic therapy (any or 
by therapy) and radio therapy (any or by therapy) will be summarized relative to the total number of 
subjects in the population analyzed. All data collected on the eCRF will be presented in listings. 
Prior and concomitant medications including those ongoing at baseline will be tabulated by ATC class 
and preferred term. Number and percentage of subjects with prior medications will be provided by 
treatment group and for all subjects combined. Other details, including medication verbatim and coding, 
will be presented in listings. A glossary of all medications will also be provided. Rescue therapy will be 
similarly described. 
Myelotoxic chemotherapy administration on cycle day 1 will be tabulated for each agent. The percentages 
of subjects administered each dose level of docetaxel and doxorubicin (TA chemotherapy) will be 
summarized relative to the safety analysis population for all subjects. Exact dose and timing will be 
provided in listings. 
Chemotherapy and steroid administration data during the study will be listed. 
7.4 
Efficacy Analyses 
All testing will be two-sided, with “statistical significance” defined as a corresponding p-value < 0.05, 
with the exception of the fallback hierarchical testing of the secondary endpoints whose “statistical 
significance” is defined in section 3.4. The fallback method of testing the secondary endpoints will be 
employed in order to retain the type I error rate if superiority is observed in the primary analysis. 
The analyses of the secondary endpoints will be carried out in the hierarchical order shown in section 3.4 
to account for multiplicity in the testing of each. Each hierarchical testing sequence will permit the 
conservation of type 1 error within each of the two active treatment group comparisons.  


 
 
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For visual comparison of the effectiveness of the F-627 dose to Placebo, the logarithm of mean and 
median for observed ANC values over time (day) for each group will be plotted for cycle 1. 
7.4.1 
Primary Efficacy 
The primary objective of this study will be to evaluate the efficacy of F-627 given as a single fixed dose 
(20 mg) as compared to placebo in the first chemotherapy cycle. The primary endpoint will be the 
duration in days of grade 4 (severe) neutropenia (ANC < 0.5 x 109/L) observed in chemotherapy cycle 1. 
A superiority analysis will be performed to compare the F-627 arm to Placebo with respect to the duration 
of severe neutropenia.  
The duration of grade 4 neutropenia in cycle 1 will be summarized descriptively by treatment group and 
for all subjects in the ITT analysis population as the number of days ANC <0.5x 109/L. The difference in 
mean duration of neutropenia between each of the Placebo and F-627 for cycle 1 will be calculated as: 
mean (Placebo) - mean (F-627). Mean duration of grade 4 neutropenia in cycle 1 between Placebo vs F-
627 will be compared using two sample t tests at significant level of 0.05.  
ANC Assessment Window 
ANC are to be measured daily beginning on day 2 of cycle 1 until ANC ≥ 2.0 × 109/L post-nadir, and then 
three days thereafter up to day 21. Subjects are expected to experience neutropenia  and recover (recovery 
defined as an ANC ≥2.0 × 109/L after the expected ANC nadir) during the first 12 days of Cycle 1. So we 
will use Day 2 to Day 12 for ANC assessment window unless the subject does not recover within the first 
12 days. If the subject did not recover within the first 12 days,  we will expand the assessment window 
until recovery, or Day 21. ANC values observed outside the assessment window will not be imputed or 
sumumarized.  
7.4.1.1 Prevention and Treatment of Missing Data  
To observe ANC behavior, blood is drawn daily post-chemotherapy until ANC levels reach ≥2.0 × 109/L, 
post-nadir and then three days later. The duration of grade 4 neutropenia is then calculated using the 
reported ANC levels.  
Every effort will be made to minimize the number of missing values for the ANC values. Local blood 
samples were collected and will be used for the analysis when the central lab ANC values are not 
available.  
Not many missing ANC values are expected. However, a small number of missing ANC data may be 
caused by subjects skipping intermediate visits or ANC samples not usable for evaluation (intermittent 
missing) from both central lab and local lab. Also, a small number of subjects may discontinue from the 
trial entirely or miss the rest of the visits for chemotherapy cycle 1 (monotone missing). The missing of 
some ANC values does not always indicate missing data from the primary endpoint. Under the following 
two scenarios, either a simple rule will be followed or no imputation of missing ANC values is needed 
when calculating the duration of grade 4 neutropenia. 
a. 
Intermittent Missing When Immediate Adjacent Values Are Both Below the Cut-off of ANC 
Level 
If the intermittent ANC missing are during the ANC assessment window (Day 1 to Day 12 of a cycle) and 
the two immediate adjacent values are both below the cutoff of ANC level (i.e. < 0.5 × 109/L), all the 
intermittent missing should be considered as below the cutoff of ANC level and will be assumed/imputed 


 
 
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to be the worst of the two adjacent values in the calculation of duration of neutropenia. These assumed 
values will be treated as observed and will not be imputed again using multiple imputations discussed in 
the next section. 
b. 
Monotone Missing When ANC Level is ≥2.0 × 109/L Post-nadir 
If a subject discontinues from the trial entirely or misses the remaining visits for chemotherapy cycle 1, 
but the last ANC value is ≥2.0 × 109/L post-nadir, then the duration of neutropenia can be calculated with 
the ANC assessments before the dropout. The remaining of the ANC value can be assumed to be the last 
observed ANC value carried forward. These assumed values will not be replaced by the imputed values 
when performing the model-based sensitivity analysis (discussed in the next section).  
The number and percentage of missing ANC values imputed using rule a, rule b, and rules a and b 
together will be summarized by treatment. Chi-square tests at 20% significance level will be performed to 
determine if there are significant differences between the two treatment arms with respect to the number 
of data points imputed by each rule or both rules combined. If there are differences shown by the test 
statistics, additional sensitivity analyses will be performed to evaluate if any bias was introduced using 
these imputation rules.  
The number and percentage of missing ANC values imputed using rule a, rule b, and rules a and b 
together will be summarized by treatment. Chi-square tests at 20% significance level will be performed to 
determine if there are significant differences between the two treatment arms with respect to the 
percentage of subjects with impution by each rule or both rules combined. If there are differences shown 
by the test statistics, additional sensitivity analyses will be performed to evaluate if any bias was 
introduced using these imputation rules.  
The sensitivity analyses of pattern mixture model and tipping point analysis are to evaluate the robustness 
of the primary efficacy results with respect to missing values using multiple imputation methods. They 
are described in detail in section 7.4.1.3.3 and 7.4.1.3.4. These sensitivity analyses are not planned to re-
impute the missing values handled by rules a and b. However, if there are differences between the two 
treatment arms as determined by the Chi-square test statistics mentioned above, these data points will be 
re-imputed as part of a sensitivity analysis for rule a, rule b, or rules a and b combined. 
In addition, missing data on Cycle 1 Day 1 will not be imputed since the ANC measurements was taken 
before chemotherapy and the subject would not be in the neutrophia before the chemotherapy.  
7.4.1.2 Multiple Imputations for Primary Analysis 
After application of the above two rules in section 7.4.1.1, the remaining missing ANC values will be 
imputed with multiple imputation (MI) methods.  
Intermittent missing ANC values will be imputed prior to the imputation of the monotone ANC values 
using the Monte Carlo Markov Chain (MCMC) approach. The imputation will be implemented separately 
for each treatment and if there was prior chemotherapy (Yes/No), under the assumption that different 
treatments and a difference in prior chemotherapy may have distinct posterior distributions. The 
imputation will include the first 12 days of ANC values post-chemotherapy, with age and baseline ANC 
values as covariates. 
MCMC method may not be appropriate when there are a large number of intermittent missing values. We 
will use MCMC method to impute when there are 4 or less intermittent missing ANC values within the 


 
 
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first 12 days of a cycle. If there are more than 4 intermittent missing ANC values, these will be imputed 
as the lowest non-imputed ANC value for that cycle day amongst all subjects from that treatment group. 
Monotone missing ANC values will be imputed with a sequential regression approach. This sequential 
approach was introduced by Rubin12 and is considered to perform well in practice with monotone 
missingness even when normality assumptions do not hold7,14,15. The monotone missing ANC values will 
be imputed in a sequential manner using regression models with a number of predictor variables. 
Covariates to be included in the model are age, prior chemotherapy, treatment group, and baseline ANC 
value in addition to the observed or imputed values of the previous days. For example, the earliest day 
will be imputed first, then the next one, and so on using outcomes from previous days as additional 
predictors.  
The steps of performing a sequential regression imputation are as following: 
i. 
If there are any missing values at Day 2 (Cycle 1 Day 2 for ANC value), it will be imputed 
using a regression based MI method for monotone missingness. Covariates included in the 
model are age, prior chemotherapy, treatment group, and baseline ANC value.  
ii. 
All remaining missing days will be imputed sequentially by the same regression, with 
covariates specified above in Step (i) and the lag values (including the imputed values) from 
earlier days.  
iii. 
Use the multiply-imputed datasets of ANC values to compute multiple durations of grade 4 
(severe) neutropenia. 
iv. 
Perform the analysis (t-test) with each of imputed duration of grade 4 neutropenia and 
combine the results (mean differences and standard errors from multiple t-tests) based on a 
standard MI methodology12. 
100 independent imputations will be done with SAS PROC MI. The resulting 100 estimates of the 
treatment differences and standard errors will then be combined into the final estimate using SAS PROC 
MIANALYZE. Sample SAS codes for the multiple imputations are provided in Appendix 2. 
7.4.1.3 Sensitivity Analyses 
A number of sensitivity analyses are planned to evaluate the robustness of the primary efficacy results. 
7.4.1.3.1 Per Protocol (PP) Population Analysis 
Sensitivity analyses for the primary efficacy endpoint will be conducted using the PP population. Major 
protocol deviations and subjects (or data) excluded from the PP Analysis Set will be defined by the 
Sponsor in a blinded manner prior to database lock. No imputation will be performed for PP analysis 
since the ANC profiles with missing ANC values that characterized neutropenia will be excluded from 
the PP analysis set.   
7.4.1.3.2 Normality Testing with Bootstrap-Resampling  
The assumption of normality in the duration of Grade 4 neutropenia will be checked by visually 
inspecting the distribution of the data along with the results from the Shapiro-Wilk normality test. If the 
assumption of normality is not met, a bootstrap-resampling method will be implemented to test the 
treatment comparisons as a sensitivity analysis. Data of duration of Grade 4 neutropenia for the two 


 
 
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treatment groups will be re-sampled independently with a total of 10,000 bootstrap replications. The 
treatment difference and associated 95% CI will be presented. 
7.4.1.3.3 Pattern Mixture Model 
Patterns of Missingness 
Understanding the reasons why data are missing is important to correctly handle the remaining data. If the 
missing data mechanism is independent of missing outcome values, conditional on the observed ones, the 
outcome values are missing at random (MAR). If the probability of missingness depends on an outside 
variable not in the model or is related to unobserved outcome values at the time of dropout and possibly 
afterward then the values are missing not at random (MNAR). As a result MNAR missing outcome values 
may not be reliably imputed using observed measurements and explicit modeling of the dropout 
mechanism may be needed. 
In this trial, reasons for missing intermittent ANC values and reasons for discontinuation are captured on 
the eCRF and will be classified as either MAR or MNAR. Table 2 summarizes the classification with the 
potential reasons. All unknown reasons for missing ANC visits/values will be considered as MNAR.  
Table 2 Classification of Missing Data Pattern 
Missing Data Pattern 
Reason of ANC Missingness 
Intermittent 
Monotone  
Missing at Random 
(MAR) 
• Missing ANC due to non-health 
related reasons 
• Not collected/reported due to 
technical difficulties 
• Subject early discontinued due to 
non-safety/efficacy related reasons.  
Missing Not at Random 
(MNAR) 
• Missing ANC due to health 
related reasons 
• Not collected due to subject’s 
health status 
• Unknown 
• Subject early discontinued due to 
AE or Investigator decision (safety 
or efficacy related reason)   
• Unknown 
 
Patterns of missing ANC values across visits will be summarized with numbers and percentages by 
treatment. All reasons for missing values will be listed and summarized.   
Pattern Mixture Models with Delta Adjustment 
To evaluate the impact of different patterns of missing ANC values, pattern-mixture models (PMMs) with 
delta adjustment will be used in this study as part of sensitivity analysis on the ITT population. PMMs 
have the advantages of allowing transparent and clinically interpretable formulations of the assumptions 
regarding unobserved data 7(Little and Rubin 2002).  
The pattern of interest for the analysis is ANC missing values not at random (MNAR) for F-627 arm. For 
purposes of the sensitivity analyses, we can define two patterns: F-627 MNAR and Others. The 
assumption is that, subjects from F-627 arm, who have an MNAR ANC value at a given day, would have, 


 
 
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on average, their unobserved ANC values worse by some amount δ compared with the observed ANC 
values of the other subjects. Subjects who have “Others” pattern of missing ANC value are treated as if 
they would have exhibited similar ANC pattern compared to other subjects on the study with observed 
values for that time point. No δ adjustment will be applied to missing ANC values from the “Others” 
pattern. 
The details for implementation of a sensitivity analysis within the PMM framework were summarized by 
Ratitch et al. (2013)8 and are described below as implemented for this study. Multiple imputation (MI) 
methods for imputing missing data available in SAS PROC MI will be incorporated. Using MI as an 
integral part of a PMM-based analysis has an advantage in that MI procedures produce correct variance 
estimates that account for uncertainty associated with the imputation process.  
It is expected that a small amount of intermittent ANC missing data will be present. Assumed values for 
the intermittent missingness will be applied where allowable (see section 7.4.1.1). The remaining 
intermittent missing data will be imputed prior to the imputation of the monotone missing data. 
Intermittent missing data classified as MNAR in F-627 arm will be imputed using the Monte Carlo 
Markov Chain (MCMC) approach and then the imputed values will be decreased by delta as defined in 
the following section. Intermittent missing data classified as MAR in F-627 arm or in the Placebo arm 
will be imputed using MCMC imputation without decreasing the imputed values by delta. Using the 
MCMC approach, missing visits will be imputed from the posterior distributions, derived from the joint 
distribution of ANC values at all visits within each treatment. Besides the treatment, there will be no 
conditioning on the covariates for this intermittent imputation.  
It is also expected that some of missing data will be caused by subjects discontinuing from the trial 
prematurely (monotone missing). For datasets with monotone missingness, regression-based imputation 
methods for monotone missingness (Rubin, 1987)12 will be applied and has the flexibility that it may be 
performed in a sequential manner using generalized regression models with a number of predictor 
variables. Covariates include in the regression models are age, prior chemotherapy, treatment group, 
baseline ANC value and previous ANC values observed. The predictor variables are the observed or 
imputed outcomes from previous days. For example, the earliest day will be imputed first, then the next 
one, and so on using outcomes from previous days as predictors. This sequential approach is considered 
to perform well with monotone missingness even when normality assumptions do not hold7,14,15. 
Sequential regression-based MI procedure was suggested for the implementation of the delta-adjustment 
strategy in the National Research Council (NRC) report on missing data (National Research Council of 
National Academy of Sciences, 2010) 16 so that timepoints are imputed one at a time and that δ 
adjustment can be propagated through time by using the adjusted values as predictors. This procedure 
follows the general principles of PMM with identifying restrictions (assumptions) discussed above and is 
summarized as follows: 
i. 
If there are any missing values at timepoint 1 (Cycle 1 Day 2 for ANC value), it will be imputed 
using a regression based MI method for monotone missingness (100 iterations per delta). 
Covariates included in the modelling are age, prior chemotherapy, treatment group, and baseline 
ANC value. At this stage, the imputed values will not yet be δ-adjusted for any subjects in the F-
627 MNAR pattern.  
ii. After imputations are obtained in Step (i), for subjects missing data at timepoint 1 in the F-627 
MNAR pattern, the imputed value at timepoint 1 will be made worse by a value of δ. Since lower 
ANC value for this study indicates worsen for the primary endpoints, δ will be subtracted from 
the previously imputed value. No adjustments will be made for the other pattern. 


 
 
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iii. All remaining timepoints will be imputed sequentially by repeating Steps (i–ii) for each timepoint 
including lag values from earlier timepoints in the imputation model (lag values will include 
imputed values from the previous step) in addition to the covariates specified above in Step (i). 
Data from subjects who have already had their responses decreased by δ in the previous step(s) 
will not be further decreased by δ again since the regression on the previous value carries this 
decrease forward. This principle also extends to the preliminary step of imputing intermittently 
missing visits. Thus, if an intermittent MNAR value is encountered for a subject, delta adjustment 
will not apply for the subsequent imputations of the monotone part of the missing visits, for that 
subject. 
iv. Use the multiply-imputed datasets of ANC values to compute the duration of grade 4 (severe) 
neutropenia. 
v. Perform the same primary analysis (t-test) with each of imputed duration of grade 4 neutropenia 
and combine the results (mean differences and standard errors from multiple t-tests) based on a 
standard MI methodology (Rubin, 1987)12. 
 
Delta values will vary from 0 to the mean value of nadir for the F-627 arm in the ITT population in 
increments of 0.005 x 109/L for ANC values. 
For each value of delta, 20 independent imputations will be done for the sensitivity analysis. The resulting 
20 estimates of the treatment differences and standard errors will then be combined into the final estimate 
for the delta, using SAS PROC MIANALYZE. Sample SAS codes for the multiple imputations are 
provided in Appendix 2. 
Figure 2 is a flow chart showing the overall methodologies associated with missing value imputation for 
the pattern mixture model with delta adjustment.  
 


 
 
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Figure 2 Missing ANC Value Imputation for Sensitivity Analysis
 
 
Primary Analysis vs Sensitivity Analysis 
The National Research Council (NRC) report on missing data16 suggests to not overburden the primary 
analysis when the primary analysis assumes MAR and leave the sensitivity analysis to MNAR models 
that deviate from MAR. In this trial, the missing ANC values are presumably very minimal and mainly 
MAR. Under this assumption, we will not use PMM for the primary analysis. The primary analysis is 
essentially a special case of above-mentioned pattern mixture model without delta adjustment (or δ = 0).   
As a result, the primary analysis and sensitivity analysis of PMM will be implemented in the same way 
and only one set of SAS sample programs is provided in Appendix 2.     
7.4.1.3.4 Tipping Point Analysis 
During the pattern mixture model with delta adjustment, delta values will vary from 0 to the mean value 
of nadir for the F-627 arm in ITT population in increments of 0.005 x 109/L for ANC value. If during the 
course of Delta change, the study conclusions change from favorable to unfavorable for F-627 arm, a 
tipping point is reached. 


 
 
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A tipping point corresponds to the delta value when the lower bound of the confidence interval is no 
longer above 0. If a tipping point is observed, delta increments will be chosen to be 0.001 x 109/L for 
ANC values with the intent to refine the grid around the tipping point.  
7.4.1.3.5 Multiple Imputation With Fully Conditional Specification (FCS) Method 
In the primary analysis, intermittent missing ANC values will be imputed with MCMC method and 
monotone missing values will be imputed with sequential regression method. To evaluate the robustness 
of the primary imputation method, a multiple imputation with fully conditional specification (FCS) 
method will be used since this method does not assume monotonicity. FCS methods can be used to 
impute missing values for variables with an arbitrary missing data pattern, assuming the existence of a 
joint distribution for these variables. Both intermittent and monotone missing ANC values will be 
imputed in the same way with a regression method. As the primary analysis, the regression will include 
the covariates age, prior chemotherapy, treatment group, and baseline ANC value. Also similar to primary 
analysis, the missing values will be imputed sequentially, with all previous timepoints included as 
additional covariates.  
10 independent imputations will be done with SAS PROC MI. The resulting 10 estimates of the treatment 
differences and standard errors will then be combined into the final estimate using SAS PROC 
MIANALYZE in the same way as the primary analysis. Sample SAS codes for the multiple imputations 
with FCS method are provided in Appendix 2. 
 
7.4.2 
Key Secondary Efficacy 
If superiority is observed in the primary analysis, a fallback testing method of the key secondary 
endpoints will be employed in order to retain the type 1 error rate. The fall back method will be used to 
test the significance of key secondary endpoints between the two treatment groups. The order of the 
testing and the assigned α are detailed in Section 3.4 and are listed as follows: 
1. The incidence rate of febrile neutropenia for chemotherapy cycle 1. α=0.04. 
2. The incidence rate of infection for chemotherapy cycle 1. α=0.005. 
3. The duration in days of grade 3 neutropenia for chemotherapy cycle 1. α=0.001. 
4. The duration in days of grade 2 neutropenia for chemotherapy cycle 1. α=0.001. 
5. The incidence rate of use of antibiotic for chemotherapy cycle 1. α=0.001. 
6. The incidence rate of use of pain medications for chemotherapy cycle 1. α=0.001. 
7. The incidence rate of grade 4 neutropenia for chemotherapy cycle 1. α=0.001. 
 
Once F-627 proves superior to Placebo, the first secondary endpoint listed above will be tested using 
significant level of α=0.04. If this comparison demonstrates superiority then the second secondary 
endpoint will be tested using a significance level of α= (0.04+0.005) =0.045, otherwise second secondary 
endpoint will be tested at α= 0. 005 as indicated in Section 3.4. This method provides an opportunity to 
test all secondary endpoints while avoiding type I error.  
All continuous key secondary endpoints will be test using the two sample t test similar to the primary 
analysis. All categorical key secondary end points will use the Chi-square test to calculate p-values for 
comparisons between treatments. If the number of events in one category is less than 5, Fisher’s exact test 
will be used in place of Chi-square.  


 
 
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Incidence of febrile neutropenia for chemotherapy cycle 1: 
The frequency and percentage of subjects with febrile neutropenia will be summarized for chemotherapy 
cycle 1. The difference in frequency between the Placebo and F-627 groups will be tested by Chi-square 
test and if the frequencies are less than 5 the difference will be tested using Fisher’s exact test. 
Incidence rate of infections for chemotherapy cycle 1: 
The number and percentage of subjects with infections will be summarized for chemotherapy cycle1. The 
difference in percentage between the F-627 and Placebo groups will be tested by a Chi-Square test. 
Duration of grade 2 and 3 neutropenia for chemotherapy cycle 1: 
The duration of grade 2 and 3 neutropenia within 12 days of chemotherapy treatment for the 
chemotherapy cycle 1 will be summarized for F-627 and Placebo. The duration of grade 2 and 3 
neutropenia within 12 days of chemotherapy treatment cycle 1 will be tested by using a t-test or, if the 
data is not normally distributed, a Wilcoxon rank-sum test. 
The incidence rate of use of antibiotics medications for chemotherapy cycle 1: 
The durations of antibiotic medication use will be summarized for chemotherapy cycle 1. The differences 
in duration between Placebo and F-627 groups in chemotherapy cycle 1 will be tested using a t-test or, if 
the data are not normally distributed, a Wilcoxon rank-sum test. 
The frequency and percentage of subjects using antibiotics medications will be summarized. The 
differences in percentage between the F-627 and Placebo groups will be tested by a chi-square test; if the 
number of events observed is less than 5, this difference will be tested using Fisher’s exact test. 
The incidence rate of use of pain medications for chemotherapy cycle 1: 
The durations of pain medication use will be summarized for chemotherapy cycle 1. The differences in 
duration between Placebo and F-627 groups in chemotherapy cycle 1 will be tested using a t-test or, if the 
data are not normally distributed, a Wilcoxon rank-sum test. 
The frequency and percentage of subjects using pain medications will be summarized. The differences in 
percentage between the Placebo and F-627 groups will be tested by a chi-square test; if the number of 
events observed is less than 5, this difference will be tested using Fisher’s exact test. 
Incidence rate of grade 4 neutropenia for chemotherapy cycle 1: 
The frequency and percentage of grade 4 neutropenia for chemotherapy cycle 1 will be summarized. The 
incidence difference of grade 4 neutropenia between Placebo and F-627 groups will be tested by Chi-
square test and if the frequencies were less than 5 the difference will be tested using Fisher’s exact test for 
cycle 1. 
7.4.2.1 Missing Data Handling for Secondary Efficacy Endpoints 
In analyzing the incidences of antibiotics and pain medications, missing data will be maintained as 
missing unless specified otherwise. Every effort will be made to ensure there is no missing start or end 
dates for antibiotics or pain medications. Therefore, no missing data imputation will be implemented for 
secondary endpoints related to IV antibiotics or hospitalizations.  
Incidence of febrile neutropenia and infection are identified through adverse events and will not be 
missing throughout the study. 


 
 
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7.4.2.2 
Sensitivity Analyses 
7.4.2.2.1 Per Protocol (PP) Population Analysis  
All key secondary endpoints will be analyzed using PP population. Major protocol deviations and 
subjects (or data) excluded from the PP Analysis Set will be defined by the Sponsor in a blinded manner 
prior to database lock. No imputation will be performed for PP analysis.   
7.4.2.2.1 Missing ANC values Analysis 
Mutiple Imputation will be performed to evaluate the impact of missing ANC values for the primary 
endpoints, similar missing data analysis (mutiple imputation without delta adjustment) will be performed 
for the the incidence rate of grade 4 neutropenia, if the testing result of the endpoint is positive.  
7.4.2.2.2 Impact of Dropouts Analysis 
For incident rates type of key secondary endpoints, there might be a small number of dropouts who have 
less exposure of chemotherapy and study drug. To evaluate the impact of these dropouts, negative 
binomial regression will be used for these endpoints as the sensitivity analysis. SAS procedure GENMOD 
will be used and the incident rate ratio between Placebo and F-627 will be estimated with confidence 
interval. The sample SAS codes are provided in Appendix 2.  
7.4.3 
Other Secondary Efficacy  
Duration of grade 4 neutropenia for chemotherapy cycle 2-4 and over all cycles: 
The duration of grade 4 neutropenia within 12 days of chemotherapy treatment for each chemotherapy 
cycle and over all cycles will be summarized for F-627 and Placebo. The over all duration of grade 4  
neutropenia within 12 days of each chemotherapy treatment cycles will be tested by using a t-test or, if 
the data is not normally distributed, a Wilcoxon rank-sum test. 
Over all duration of grade 4 neutropenia= Average (duration of grade 4 neutropenia for Cycle 1 to 4). 
Duration of grade 2 and 3 neutropenia for chemotherapy cycle 2-4 and over all cycles: 
The duration of grade 2, 3 and 4 neutropenia within 12 days of chemotherapy treatment for each 
chemotherapy cycle and overall cycles will be summerized for F-627 and Placebo. The duration of grade 
2 and 3 neutropenia within 12 days of each chemotherapy treatment cycle and over all cycles will be 
tested by using a t-test or, if the data is not normally distributed, a Wilcoxon rank-sum test.  
Incidence of febrile neutropenia for chemotherapy cycle 2-4 and over all cycles: 
The frequency and percentage of subjects with febrile neutropenia will be summarized for each treatment 
arm for each chemotherapy cycle and over all cycles.  
The incidence of febrile neutropenia over all cycles is any incidences occurred in cycle 1 to cycle 4. 
Time to recovery from ANC Nadir post chemotherapy: 
Difference in number of days of ANC recovery (ANC ≥2.0 × 109/L) from ANC nadir between F-627 and 
Placebo in each chemotherapy cycle and over all cycles will also be compared using Chi squared test. 
The time to recovery from ANC Nadir over all cycles will be the average of time to recovery from cycle 1 
to cycle 4. 


 
 
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Depth of ANC nadir:  
The lowest ANC values within 12 days of chemotherapy treatment will be summarized for each cycle. 
Difference in ratio of ANC nadir between F-627 and Placebo will be calculated by Chi squared test for 
each cycle and over all cycles. 
Ratio to Placebo = ANC nadir value of F-267 group/ANC nadir value of Placebo group 
The incidence rate of use of antibiotics and pain medications for chemotherapy cycle 2-4 and over 
all cycles: 
The durations of antibiotic and pain medication use will be summarized for each cycle and over all cycles. 
The differences in duration between F-627 and Placebo groups in each chemotherapy cycle and over all 
cycles will be tested using a t-test or, if the data are not normally distributed, a Wilcoxon rank-sum test. 
The frequency and percentage of subjects using antibiotics and pain medications will be summarized for 
each cycle and over all cycles. The differences in percentage between the F-627 and Placebo groups will 
be tested by a chi-square test; if the number of events observed is less than 5, this difference will be tested 
using Fisher’s exact test. 
Incidence rate of infections for chemotherapy cycle 2-4 and over all cycles: 
The number and percentage of subjects with infections will be summarized for each cycle and over all 
cycles. The difference in percentage between the F-627 and Placebo groups will be tested by a Chi-
Square test. 
The incidence rate of grade 4 (severe) neutropenia for chemotherapy cycles 2, 3, 4 and over all 
cycles. 
The number and percentage of subjects with grade 4 (severe) neutropenia will be summarized for each 
cycle and over all cycles. The difference in percentage between the F-627 and Placebo groups will be 
tested by a Chi-Square test. 
 
The incidence rate of grade 2(mild), grade 3(moderate) neutropenia for chemotherapy cycles 1, 2, 3, 
4 and over all cycles. 
The number and percentage of subjects with grade 2(mild), grade 3(moderate)  will be summarized for 
each cycle and over all cycles. The difference in percentage between the F-627 and Placebo groups will 
be tested by a Chi-Square test. 
ECG:  
Change-from-baseline in heart rate, PR, QRS and QTcF intervals will be summarized for each cycle and 
overall cycles. Categorical outliers and T-wave morphology changes on treatment will be summarized for 
each cycle and over all cycles. 
7.5 
Safety Analyses 
All safety analysis will be based on the actual treatment received for the safety analysis population. Safety 
parameters include AEs, clinical laboratory parameters (hematology, blood chemistry and urinalysis), 
vital signs, ECG parameters, and other relevant safety measures (physical examination, concomitant 


 
 
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medications, and pregnancy test and physical exam). Summaries of safety parameters will be presented by 
treatment group.  
Wherever applicable for a safety parameter, the last assessment made before the first dose of 
chemotherapy in Cycle 1 will be used as the baseline for all analyses of that safety parameter.  
In case of repeated measurements at a given timepoint, the latest value will be used for analysis. 
Measurements at unscheduled visits will only be listed, unless it is actually a repeat of the scheduled 
measurement.  
7.5.1 
Extent of Exposure to Study Medication 
Descriptive statistics will be presented for the number of chemotherapy treatments cycle (up to four), 
treatment duration (weeks), total dose received and dose intensity. Frequencies of subjects will be 
provided for dose intensity categories. 
7.5.2 
Adverse Events 
Analysis of adverse events will be carried out on the safety population. All adverse events will be 
included in the analyses, summaries, and individual subject data listings.  
A TEAE overview summary table will be provided by treatment group and for all subjects including the 
number and percentage of subjects reporting at least one TEAE and the number of TEAEs reported for 
the following categories: 
• 
Any TEAEs 
• 
Serious TEAEs  
• 
Febrile neutropenia 
• 
Injection site reaction 
• 
TEAE leading to death  
• 
TEAE leading to study drug interruption 
• 
TEAE leading to discontinuation of study drug 
• 
TEAE leading to study discontinuation  
 
7.5.2.1 
Incidence of Adverse Events 
TEAEs will be summarized by treatment group by system organ class (SOC) and preferred term (PT). 
The summary tables will display the total number and percentage of subjects reporting a specific TEAE, 
and the number of TEAE reported. TEAEs will be presented by system organ class (SOC) sorted 
alphabetically and preferred term (PT) sorted in decreasing frequency of occurrence. 
Summary tables will be prepared for: 
• 
Summary of TEAEs (including Febrile neutropenia and Injection site reaction) 
• 
All TEAEs 
• 
Serious TEAEs 
• 
Treatment-related TEAEs 
• 
TEAE leading to study discontinuation 
• 
TEAEs by NCI-CTCAE grade 


 
 
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• 
Common TEAEs with > 5% incidence rate in any treatment group 
Supporting data listings will be provided by chemotherapy regimen and treatment group, including: 
• 
All adverse events (including any AEs reported in the study)  
• 
Serious adverse events  
• 
Adverse events leading to death 
• 
Adverse events for subjects who discontinued the study due to AE 
• 
Adverse events of special interest (Febrile Neutropenia) 
• 
Adverse events of special interest (Infections) 
• 
Glossaries of Preferred terms to verbatim by System Organ Class (SOC) 
Injection site reactions details will be summarized similarly by parameter and timepoint for each cycle 
and all cycles combined. 
7.5.3 
Laboratory Data 
For the analysis purpose, the study visit/timepoint will be recalculated using the dates of Relative Day 1 
collected from Myelotoxic Chemotherapy eCRF page for each cycle. 
Descriptive statistics will be presented for value at baseline and change from baseline at cycles 1-4 
Relative Day 2 and end-of-study for each continuous laboratory parameter. Number and percentage of 
subjects with clinically significant laboratory abnormalities in hematology, chemistry and urinalysis 
parameters will be summarized for low and high categories by treatment group. 
Shift tables from baseline grade to post-baseline highest grade will be presented for clinical laboratory 
measurements (serum chemistry and hematology) by treatment group. Shift tables for urinalysis will be 
presented by normal, abnormal based on the investigator-assessed clinically significant laboratory 
abnormalities. 
All data will be all displayed in subject data listings for all safety subjects. 
7.5.4 
Vital Signs 
Descriptive statistics will be prepared for vital signs value at visit and change from baseline. All data will 
be all displayed in subject data listings for all safety subjects. 
7.5.5 
Electrocardiogram 
Descriptive statistics will be prepared for selected ECG parameters as mentioned in section 6.4.6 at visit 
and change from baseline. All the other parameters will be listed. 
7.5.6 
Other Safety Assessments 
Physical examination and pregnancy test, results will be presented in listings for all Safety subjects. 
8. CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
No changes are planned from the protocol. 


 
 
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9. STATISTICAL SOFTWARE 
All analyses will be done using SAS version 9.4. 
10. REFERENCES 
1. Dmitrienko, A., Tamhane, A.C. and Bretz, F. (2009), Multiple Testing Problems in 
Pharmaceutical Statistics, Boca Raton, FL: Taylor & Francis/CRC Press. 
2. Dmitrienko, Offen, Westfall. (2003). Gatekeeping strategies for clinical trials that do not require 
all primary effects to be significant. Statistics in Medicine. 22, 2387-2400. 
3. Marcus R, Peritz E, Gabriel KR. (1976). On closed testing procedure with special reference to 
ordered analysis of variance. Biometrika. 63, 655-660. 
4. Westfall, Krishen. (2001). Optimally weighted, fixed sequence, and gatekeeping multiple testing 
procedures. Journal of Statistical Planning and Inference. 99, 25-40 
5. Wiens BL, Dmitrienko A. The fallback procedure for evaluating single family of hypotheses. J 
Biopham Stat. (2005);15(6):929-42 
6. U.S Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) Draft 
Guidance, Multiple Endpoints in Clinical Trials, Guidance for Industry. January 2017. 
7. Little RJA, Rubin DB. Statistical analysis with missing data, (2nd edn). John Wiley and Sons, 
Inc.: New York, 2002. 
8. Ratitch B, O’Kelley M, and Tosiello R. Missing data in clinical trials: from clinical assumptions 
to statistical analysis using pattern mixture models. Pharmaceutical Statistics, 2013 
(wileyonlinelibrary.com) DOI: 10.1002/pst. 1549 
9. Heitjan, F. and Little, R. J. A. (1991), “Multiple Imputation for the Fatal Accident Reporting 
System,” Applied Statistics, 40, 13–29. 
10. Schenker, N. and Taylor, J. M. G. (1996), “Partially Parametric Techniques for Multiple 
Imputation,” Computational Statistics and Data Analysis, 22, 425–446. 
11. Horton, N. J. and Lipsitz, S. R. (2001), “Multiple Imputation in Practice: Comparison of Software 
Packages for Regression Models with Missing Variables,” American Statistician, 55, 244–254. 
12. Rubin DB. M. Multiple imputation for nonresponse in surveys. John Wiley and Sons, Inc.: New 
York, 1987. 
13. Little RJA, Rubin DB. Statistical analysis with missing data, (2nd edn). John Wiley and Sons, 
Inc.: New York, 2002. 
14. Molenberghs G, Kenward MG. Missing data in clinical studies. John Wiley and Sons, Inc.: New 
York, 2007. 
15. White IR, Royston P, Wood AM. Multiple imputation using chained equations:Issues and 
guidance for practice. Statistics in Medicine, 2011 DOI: 10.1002/sim.4067 
16. National Research Council, The Prevention And Treatment Of Missing Data In Clinical Trials, 
2010 










 
 
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APPENDIX 4  
 REFERENCE RANGES FOR LABORATORY ABNORMALITIES 
Table 1 Central Laboratory Reference Range 
 
 
Central Laboratory Reference Range 
Variable 
Units 
Low (<) 
High(>) 
Hematology 
Hemoglobin 
g/L 
115 
160 
Hematocrit 
Ratio 
0.364 
0.489 
WBC 
109/L 
4.5 
11.0 
RBC 
1012/L 
3.8 
5.2 
CD34 
/uL 
5 
11 
Mean 
corpuscular 
volume 
fL 
83 
104 
Mean 
corpuscular 
hemoglobin 
pg 
26.0 
34.0 
Mean 
corpuscular 
concentration 
g/L 
307 
346 
Red Cell 
Distribution 
Width 
% 
Not applicable 
15.0 
Platelets 
109/L 
130 
400 
Mean Platelet 
Volume 
fL 
7.5 
12.0 
Absolute Count 
Neutrophils 
109/L 
1.8 
7.7 
Lymphocytes 
109/L 
1.0 
4.8 
Monocytes 
109/L 
0.1 
0.8 
Eosinophils 
109/L 
Not applicable  
0.5 
Basophils 
109/L 
Not applicable 
0.2 
Neutrophils 
% 
40.0 
70.0 
Lymphocytes 
% 
22.2 
43.6 
Neutrophils Band 
Form/Leukocytes 
% 
0 
7 
CD34 
% 
0.06 
0.14 
Segs 
% 
36 
66 
Monocytes 
% 
2.0 
12.0 
Eosinophils 
% 
Not applicable 
4.5 
Basophils 
% 
Not applicable 
1.8 
Clinical Chemistry 
ALT  
U/L 
Not applicable  
33 
ALP 
U/L 
42 
98 


 
 
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Central Laboratory Reference Range 
Variable 
Units 
Low (<) 
High(>) 
AST  
U/L 
14 
34 
Bicarbonate 
mmol/L 
20 
31 
Bilirubin, total 
µmol/L 
5.1 
20.5 
Urea 
Mmol/L 
3.2 
8.2 
Calcium 
mmol/L 
2.15 
2.55 
Chloride(Cl) 
mmol/L 
99 
109 
Creatinine 
μmol/L 
44 
97 
GGT 
U/L 
Not applicable 
37 
Glucose, 
Random 
mmol/L 
3.3 
7.8 
LD 
U/L 
120 
246 
Phosphate 
mmol/L 
0.81 
1.45 
Potassium 
mmol/L 
3.5 
5.1 
Sodium 
mmol/L 
136 
145 
Urinalysis: Quantitative 
pH 
None 
5.0 
7.0 
Specific gravity 
None 
1.010 
1.030 
 
 
 
 

Prot_001.pdf: 
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 
Page 1 of58 
Version: Amendment 1.0 


_______________________________________________________________________________________________ 
 
Protocol: GC-627-04 
Proprietary and Confidential 
Page 2 of 58 
Date: 07 May 2017 
  
Version: Amendment 1.0 
 
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: _______________________ 
 
 
 
 
 
 
 
 


_______________________________________________________________________________________________ 
 
Protocol: GC-627-04 
Proprietary and Confidential 
Page 3 of 58 
Date: 07 May 2017 
  
Version: Amendment 1.0 
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 
 


_______________________________________________________________________________________________ 
 
Protocol: GC-627-04 
Proprietary and Confidential 
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Date: 07 May 2017 
  
Version: Amendment 1.0 
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. 
5.  Holmes,F.A., Jones,S.E., O'Shaughnessy,J., Vukelja,S., George,T., Savin,M., 
Richards,D., Glaspy,J., Meza,L., Cohen,G. et al 2002. Comparable efficacy and safety 
profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in 
chemotherapy-induced neutropenia: a multicenter dose-finding study in women with 
breast cancer. Ann. Oncol. 13:903-909. 
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, 
multicenter study to evaluate single administration pegfilgrastim once per cycle versus 
daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or 
stage III/IV breast cancer. J. Clin. Oncol. 20:727-731. 
7.  Green,M.D., Koelbl,H., Baselga,J., Galid,A., Guillem,V., Gascon,P., Siena,S., 
Lalisang,R.I., Samonigg,H., Clemens,M.R. et al 2003. A randomized double-blind 
multicenter phase III study of fixed-dose single-administration pegfilgrastim versus 
daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann. Oncol. 
14:29-35. 
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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Date: 07 May 2017 
  
Version: Amendment 1.0 
• 
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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Protocol: GC-627-04 
Proprietary and Confidential 
Page 53 of 58 
Date: 07 May 2017 
  
Version: Amendment 1.0 
• 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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Protocol: GC-627-04 
Proprietary and Confidential 
Page 55 of 58 
Date: 07 May 2017 
  
Version: Amendment 1.0 
 
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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Protocol: GC-627-04 
Proprietary and Confidential 
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Date: 07 May 2017 
  
Version: Amendment 1.0 
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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Protocol: GC-627-04 
Proprietary and Confidential 
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Date: 07 May 2017 
  
Version: Amendment 1.0 
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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Protocol: GC-627-04 
Proprietary and Confidential 
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Date: 07 May 2017 
  
Version: Amendment 1.0 
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