Clinical trial NCT02190721
Conditions: Neutropenia
Keywords: Neutropenia
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2015-05-12; Completion date: 2017-04-04
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of daily subcutaneous administration of 5 μg/kg tbo-filgrastim in infants, children and adolescents with solid tumors without bone marrow involvement.

Detailed description:

Arms: arm 1: Patients will receive subcutaneous doses of tbo-filgrastim 5 μg/kg body weight daily; each daily dose, to be administered at the investigative site
Interventions: intervention 1: tbo-filgrastim
Intervention descriptions: intervention 1: 5 μg/kg

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol with Amendment 02
A Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics,
Pharmacodynamics, Efficacy, and Immunogenicity of Daily Subcutaneous Administration 
of 5 μg/kg tbo-filgrastim in Infants, Children and Adolescents with Solid Tumors without 
Bone Marrow Involvement
Study XM02-ONC-201
NCT02190721
Protocol with Amendment 02 Approval Date: 24 February 2016


Pediatric Study–Chemotherapy-Induced Neutropenia
Clinical Study Protocol with Amendment 02
Study XM02-ONC-201
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Clinical Study Protocol with Amendment 02
A Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, Efficacy, and Immunogenicity of Daily Subcutaneous Administration of 
5 μg/kg tbo-filgrastim in Infants, Children and Adolescents with Solid Tumors without Bone 
Marrow Involvement
Phase 2
Study XM02-ONC-201
EudraCT number: 2014-001772-55
Protocol with Amendment 02 Approval Date: 24 February 2016
Sponsor (and Monitor)
TEVA Pharmaceutical Industries Ltd
5 Basel Street
Petach Tiqva 49131, Israel
Monitor
Authorized Representative (Signatory)
Merckle GmbH (a company of the TEVA Group)
Sponsor’s Medical Expert
Sponsor’s Safety Officer
Merckle GmbH
Ratiopharm GmbH
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed by the 
provisions of the International Conference on Harmonization (ICH); United States (US) Code of Federal Regulations 
(CFR) and European Union (EU) Directives (as applicable in the region of the study); local country regulations; and the 
sponsor’s Standard Operating Procedures (SOPs).
This document contains confidential and proprietary information (including confidential commercial information 
pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded Pharmaceutical Products R&D, Inc., 
and its affiliate, Sicor Biotech UAB (collectively the “Sponsor”). The recipient agrees that no information contained 
herein may be published or disclosed without written approval from the Sponsor.
© 2016 TEVA Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Pediatric Study–Chemotherapy-Induced Neutropenia
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AMENDMENT HISTORY
The protocol for study XM02-ONC-201 (original protocol dated 12 May 2014) has been amended 
and reissued as follows:
Amendment 01
11 January 2016
20 patients enrolled to date
Amendment 02
24 February 2016
20 patients enrolled to date
Details about the changes and rationale for each change are provided in Section 17.


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INVESTIGATOR AGREEMENT


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Clinical Study Protocol with Amendment 02
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COORDINATING INVESTIGATOR AGREEMENT


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Clinical Study Protocol with Amendment 02
Study XM02-ONC-201
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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS
Central Clinical Laboratory
Bioanalytical Lab
Global Bioassays and Technology, TEVA Pharmaceuticals USA (ADA analysis)
Central Institutional Review Board
Central Electrocardiogram Evaluation
Central ECG Evaluation


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CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the physician listed below: 
Medical Support Center North America:
(24-hour access)
Medical Support Center EAPA direct: 
Email:
For operational issues, contact the operational lead listed below: 
For serious adverse events:
Send by facsimile/email to the sponsor’s local safety officer/clinical research organization. In the 
event of difficulty transmitting the form, contact the sponsor’s study personnel identified above for 
further instruction.


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CLINICAL STUDY PROTOCOL SYNOPSIS
Sponsor: TEVA Pharmaceutical Industries Ltd.
Title of Study: A Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, Efficacy, and Immunogenicity of Daily Subcutaneous Administration of 5 μg/kg tbo-filgrastim in 
Infants, Children and Adolescents with Solid Tumors without Bone Marrow Involvement
Study Number: XM02-ONC-201
EudraCT/IND Number(s): 2014-001772-55
Name of Active Ingredient: tbo-filgrastim
Name of Investigational Product: tbo-filgrastim (the investigational product in this study, has been approved as a 
biosimilar to filgrastim [Neupogen] in the European Union, under the product names Tevagrastim, Ratiograstim and 
Biograstim [international nonproprietary name: filgrastim], and has the Teva product code XM02. It has been approved 
under the product name Granix [tbo-filgrastim] in the United States of America (USA) via a Biologic License 
Application (BLA). To retain a consistent nomenclature throughout this protocol that distinguishes the investigational 
product from filgrastim [Neupogen], the investigational product is termed “tbo-filgrastim”.
Phase of Clinical Development: 2
Number of Investigational Centers Planned: Approximately 30
Countries Planned: Central and Eastern Europe, and the United States of America
Number of Patients Planned: approximately 50; minimum 30 (at least 6 in the infants group [1 month to <2 years], 12 
in the children group [2 to <12 years], and 12 in the adolescents group [12 to <16 years])
Study Population: Patients aged 1 month to <16 years with solid tumors without bone marrow involvement, who are 
scheduled to receive myelosuppressive chemotherapy (CTX)
Planned Study Period: May 2015 to November 2016
Primary Objective: The primary objective of this study is to assess the safety and tolerability of 5 µg/kg tbo-filgrastim 
in the pediatric population with solid tumors without bone marrow involvement.
Secondary Objectives: The secondary objectives of the study are to assess the pharmacokinetics using sparse sampling 
strategy, pharmacodynamics, efficacy, and immunogenicity of tbo-filgrastim in this patient population.
Diagnosis and Criteria for Inclusion: Patients may be included in the study if they meet all of the following criteria:
a.
Male or female infants, children and adolescents aged 1 month to <16 years at the time of Informed 
Consent Form signing.
b.
Patients with solid tumors without bone marrow involvement (ie, non-myeloid neoplasms), who are 
scheduled to receive myelosuppressive CTX.
c.
Body weight ≥5 kg.
d.
Written informed consent provided by parent(s)/legal representative(s) of the pediatric patient and 
patient’s assent if able to understand and/or follow study instructions alone or with parental assistance.
e.
Patients must have an initial diagnosis and histologic proof of their malignancy. Additionally, if the 
patients have a recurrence of their disease, clear radiographic or biopsy evidence is required within 
4 weeks prior to study entry. 


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f.
All enrolled subjects should have signed consent for a CTX regimen that is known to be myelotoxic, with 
counts expected to drop below the absolute neutrophil count (ANC) 0.5 × 109/L for at least 3 days. These 
regimens would include at least one of the following:
-
Etoposide
-
doxorubicin
-
ifosfamide
-
cyclophosphamide
g.
ANC and platelet count: Patients must have an ANC >1 × 109/L and a platelet count >100 × 109/L to be 
eligible for therapy at the start of CTX.
h.
Normal cardiac, renal, and hepatic function.
i.
All subjects must have a life expectancy of 12 weeks or more.
j.
Performance Status: Lansky performance score >60 (age 1 to <16 years).
k.
Fertile and sexually active patients (male or female) must use highly reliable contraceptive measures (ie, 2
of the following: oral contraception, implants, injections, barrier contraception, and intrauterine device, or 
vasectomized/sterilized partners, or sexual abstinence). For purposes of this study, a fertile female patient 
is any female patient who has experienced menarche and who has not undergone tubal ligation. 
l.
Female patients who have attained menarche must have a negative urine pregnancy test at the screening 
visit.
Criteria for Exclusion: Patients will be excluded from participating in this study if they meet 1 or more of the 
following criteria: 
a.
Bone marrow involvement.
b.
Active myelogenous leukemia or history of myelogenous leukemia.
c.
Previous treatment with colony-stimulating factors (granulocyte colony-stimulating factor [G-CSF], 
granulocyte-macrophage colony-stimulating factor, interleukin 11 [IL-11]) less than 6 weeks prior to study 
entry.
d.
Known hypersensitivity to any component of this product.
e.
History of congenital neutropenia or cyclic neutropenia. 
f.
Any illness or condition that in the opinion of the investigator may affect the safety of the patient or the 
evaluation of any study endpoint.
g.
Pregnant or nursing female patients. 
h.
Fertile patients who do not agree to use highly reliable contraceptive measures during the entire duration 
of the study.
i.
Prior bone marrow or stem cell transplant, or prior radiation to ≥25% of bone marrow (eg, whole pelvic 
radiation) for any reason, or any therapeutic radiation within the 4 weeks prior to the first tbo-filgrastim 
dose.
j.
Ongoing active infection or history of infectious disease within 2 weeks prior to the screening visit.


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k.
Treatment with lithium at screening or planned during the study.
l.
[New criterion] Participation in an interventional clinical study within 30 days or 5 half-lives of the 
investigational product before enrollment, whichever is longer.
Study Drug Dose, Mode of Administration, and Administration Rate: Tbo-filgrastim is a biosimilar of Neupogen 
filgrastim, a human G-CSF. Patients will receive subcutaneous doses of tbo-filgrastim 5 μg/kg body weight daily; each 
daily dose will be taken from a vial containing 300 µg/mL tbo-filgrastim. The first dose of tbo-filgrastim will be 
administered after 24 hours (±3 hours) following the end of myelosuppressive CTX in week 1 of the study cycle 1. 
Daily dosing with tbo-filgrastim should continue until the expected neutrophil nadir is passed and the neutrophil count 
has recovered to 2.0 × 109/L but not longer than on 14 consecutive days. A transient increase in neutrophil counts is 
typically seen 1 to 2 days after initiation of tbo-filgrastim therapy followed by the chemotherapy induced nadir. 
Method of Blinding and Randomization: open-label, no blinding
Duration of Participation: The maximum duration of the study for an individual patient (from screening period until 
the end of the 90-day follow-up period) will be approximately 18 weeks.
General Design and Methodology: This is a Phase 2, multicenter, open-label study to evaluate the safety, tolerability, 
pharmacokinetics, pharmacodynamics, efficacy, and immunogenicity of tbo-filgrastim at a dose of 5 μg/kg/day in 
infants, children and adolescents with solid tumors scheduled to receive at least 1 cycle of CTX.
The study will include 3 groups stratified by age: 1 month to <2 years; 2 to <12 years; 12 to <16 years. Recruitment of 
subjects in the youngest age stratum (1 month to <2 years) will begin only once safety (from the start of study to CTX-
day 21) and pharmacodynamic (from the start of study to day 15 [relative to first tbo-filgrastim administration]) results 
are available for a minimum of 6 subjects in the middle age stratum group and have been reviewed by the Data 
Monitoring Committee (DMC) and no significant safety signals that prevent recruitment in the youngest age stratum 
have been detected.
Safety Variables and Endpoints: The primary outcome variables and endpoints for this study are safety evaluations. 
The safety of tbo-filgrastim will be assessed by evaluating the following:

adverse event reports throughout the study

clinical laboratory test results at screening and at the end-of-study visit

vital signs measurements (blood pressure, pulse rate, respiration rate, and body temperature) at screening, 
throughout the study treatment, and at the end-of-study visit

electrocardiography findings at screening, pre-dose, and 4 and 6 hours after the first tbo-filgrastim 
administration, and at the end-of-study visit

physical examination results at screening and at the end-of-study visit

concomitant medication usage throughout the study

local tolerability at the injection site at 1 hour (±30 minutes) after each study drug injection

spleen sonography assessments at screening, on day 4 of tbo-filgrastim treatment, at the end-of-study visit,
and if the patient reports left upper abdominal and/or shoulder tip pain

anti-drug antibody assessment prior to the first tbo-filgrastim administration, at the end-of study visit, and 
at 30 days and 3 months after the last tbo-filgrastim study drug treatment in the first cycle. 

survival at 90 day follow-up. 


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Pharmacokinetic Variables and Endpoints:
The pharmacokinetic variables and endpoints for this study are as follows:

maximum observed plasma/serum drug concentration (Cmax)

time to maximum observed drug concentration (tmax)

area under the serum drug concentration by time curve from time 0 to 12 hours postdose (AUC0–12)

area under the serum concentration- time curve from time 0 to infinity (AUC0–∞)

elimination half-life (t½)
Pharmacodynamic Variables and Endpoints:
The pharmacodynamic variables and endpoints for this study are as follows: 

incidence and duration of severe neutropenia (DSN, ANC <0.5 × 109/L)

area under the curve of absolute neutrophil count (AUCANC)

ANC nadir (measured in 109/L), which is the lowest ANC recorded

time to ANC nadir from the beginning of tbo-filgrastim administration up to the occurrence of the ANC 
nadir

time to ANC nadir from the beginning of CTX up to the occurrence of the ANC nadir

time to ANC recovery to ≥1.0 × 109/L, and time to ANC recovery to ≥2.0 × 109/L from ANC nadir 

time to ANC recovery to ≥1.0 × 109/L, and time to ANC recovery to ≥2.0 × 109/L from the beginning of 
tbo-filgrastim administration and from CTX-day 1
Efficacy Endpoint: The efficacy endpoint for this study is incidence of febrile neutropenia.
Statistical Considerations: The overall sample size of 50 is considered sufficient to allow exploratory analysis. Data 
will be evaluated using statistical approaches for exploratory data analyses.


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
COORDINATING INVESTIGATOR AGREEMENT...................................................................4
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............5
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................6
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................18
1.
BACKGROUND INFORMATION...........................................................................21
1.1.
Introduction.................................................................................................................21
1.2.
Name and Description of Investigational Product......................................................22
1.3.
Findings From Nonclinical and Clinical Studies........................................................23
1.3.1.
Nonclinical Studies.....................................................................................................23
1.3.2.
Clinical Studies...........................................................................................................24
1.3.2.1.
Clinical Pharmacology and Efficacy Studies .............................................................24
1.3.2.2.
Clinical Safety Studies................................................................................................26
1.3.3.
Postmarketing Safety Data .........................................................................................28
1.4.
Known and Potential Risks and Benefits to Human Subjects....................................28
1.5.
Selection of Drugs and Dosages.................................................................................29
1.6.
Compliance Statement................................................................................................29
1.7.
Population To Be Studied...........................................................................................29
1.8.
Relevant Literature and Data......................................................................................29
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................30
2.1.
Purpose of the Study...................................................................................................30
2.2.
Study Objectives.........................................................................................................30
3.
STUDY DESIGN .......................................................................................................31
3.1.
General Design and Study Schema.............................................................................31
3.2.
Primary and Secondary Measures and Endpoints ......................................................32
3.2.1.
Safety Measures and Endpoints..................................................................................32
3.2.2.
Pharmacokinetic Measures and Endpoints .................................................................32
3.2.3.
Pharmacodynamic Measures and Endpoints ..............................................................32


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3.2.4.
Efficacy Measures and Endpoint................................................................................33
3.3.
Randomization and Blinding......................................................................................33
3.4.
Study Drugs and Dosage ............................................................................................33
3.4.1.
Investigational Product and Dosage ...........................................................................33
3.4.1.1.
Tbo-filgrastim.............................................................................................................33
3.4.1.2.
Formulation.................................................................................................................33
3.4.1.3.
Packaging, Labeling, Preparation, and Storage..........................................................33
3.4.1.4.
Dose, Route of Administration, and Schedule............................................................33
3.4.2.
Other Study Drugs and Dosage ..................................................................................34
3.5.
Duration of Patient Participation ................................................................................34
3.6.
Stopping Rules and Discontinuation Criteria .............................................................34
3.6.1.
Early Discontinuation.................................................................................................34
3.6.2.
Criteria for Withdrawal...............................................................................................35
3.6.3.
Replacement of Withdrawn Subjects..........................................................................35
3.7.
Study Drug Supply and Accountability......................................................................35
3.7.1.
Study Drug Storage and Security ...............................................................................35
3.7.2.
Study Drug Accountability.........................................................................................35
3.8.
Maintenance of Randomization and Blinding............................................................36
3.9.
Source Data Recorded on the Case Report Form.......................................................36
3.10.
Time Schedule ............................................................................................................36
3.11.
Study Procedures ........................................................................................................36
3.11.1.
Procedures for Screening and Enrollment..................................................................41
3.11.2.
Procedures Before Study Drug Treatment..................................................................42
3.11.3.
Procedures During Study Drug Treatment .................................................................42
3.11.3.1.
Day 1...........................................................................................................................42
3.11.3.2.
Day 2 to Day 15..........................................................................................................43
3.11.4.
End-of-Study Visit (CTX-Day 21 [±2 days]; prior to next CTX cycle).....................43
3.11.5.
Procedures After Study Drug Treatment ....................................................................44
3.11.6.
Unscheduled Visits .....................................................................................................44
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................45
4.1.
Patient Inclusion Criteria ............................................................................................45
4.2.
Patient Exclusion Criteria...........................................................................................46
4.3.
Withdrawal Criteria and Procedures...........................................................................46


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5.
TREATMENT OF PATIENTS..................................................................................48
5.1.
Study Drugs Administered .........................................................................................48
5.2.
Restrictions .................................................................................................................48
5.2.1.
Concomitant Medications...........................................................................................48
5.2.2.
Prescription Medications ............................................................................................48
5.2.3.
Over-the-Counter Medications and Herbal Remedies................................................48
5.2.4.
Contraceptive Measures..............................................................................................48
5.2.5.
Dietary ........................................................................................................................49
5.2.6.
Tobacco.......................................................................................................................49
5.2.7.
Exercise.......................................................................................................................49
5.3.
Prior and Concomitant Therapy or Medication..........................................................49
5.4.
Procedures for Monitoring Patient Compliance .........................................................49
5.5.
Total Blood Volume ...................................................................................................49
6.
ASSESSMENT OF SAFETY.....................................................................................51
6.1.
Adverse Events ...........................................................................................................51
6.1.1.
Definition of an Adverse Event ..................................................................................51
6.1.2.
Recording and Reporting Adverse Events..................................................................52
6.1.3.
Severity of an Adverse Event .....................................................................................52
6.1.4.
Relationship of an Adverse Event to the Study Drug.................................................53
6.1.5.
Serious Adverse Events..............................................................................................54
6.1.5.1.
Definition of a Serious Adverse Event .......................................................................54
6.1.5.2.
Expectedness...............................................................................................................54
6.1.5.3.
Reporting a Serious Adverse Event............................................................................54
6.1.6.
Protocol-Defined Adverse Events for Expedited Reporting ......................................56
6.1.7.
Withdrawal Due to an Adverse Event ........................................................................56
6.1.8.
Medical Emergencies..................................................................................................57
6.1.9.
Protocol Deviations Because of an Adverse Event ....................................................57
6.2.
Pregnancy ...................................................................................................................57
6.3.
Clinical Laboratory Tests ...........................................................................................58
6.3.1.
Serum Chemistry ........................................................................................................58
6.3.2.
Hematology.................................................................................................................59
6.3.3.
Other Clinical Laboratory Tests .................................................................................59
6.3.3.1.
Human Chorionic Gonadotropin Tests.......................................................................59


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6.4.
Vital Signs ..................................................................................................................59
6.5.
Electrocardiography....................................................................................................60
6.6.
Physical Examinations................................................................................................60
6.7.
Other Safety Measures and Variables.........................................................................60
6.7.1.
Concomitant Medication ............................................................................................60
6.7.2.
Tolerability at the Injection Site .................................................................................60
6.7.3.
Spleen Sonography.....................................................................................................61
6.7.4.
Immunogenicity Assessment......................................................................................61
6.7.5.
Survival at 90 Day Follow-up.....................................................................................61
6.8.
Methods and Timing of Assessing, Recording, and Analyzing Safety Data..............61
7.
ASSESSMENT OF PHARMACOKINETICS, PHARMACODYNAMICS, 
AND IMMUNOGENICITY.......................................................................................63
7.1.
Pharmacokinetic Assessment......................................................................................63
7.1.1.
Pharmacokinetic Variables.........................................................................................63
7.1.2.
Blood Sampling and Handling....................................................................................63
7.1.3.
Shipment of Samples..................................................................................................63
7.2.
Pharmacodynamic Variables ......................................................................................64
7.2.1.
Pharmacodynamic Variables ......................................................................................64
7.2.2.
Blood Sampling and Handling....................................................................................64
7.2.3.
Shipment of Samples..................................................................................................65
7.3.
Immunogenicity Assessment......................................................................................65
7.3.1.
Blood Sampling and Handling....................................................................................65
7.3.2.
Shipment and Analysis of Samples ............................................................................65
8.
ASSESSMENT OF EFFICACY ................................................................................67
8.1.
Efficacy Variable........................................................................................................67
8.2.
Methods and Timing of Assessing, Recording, and Analyzing Efficacy Data ..........67
9.
STATISTICS ..............................................................................................................68
9.1.
Study Design and Randomization ..............................................................................68
9.2.
Sample Size and Power Considerations .....................................................................68
9.3.
Analysis Sets/Populations...........................................................................................68
9.3.1.
Intent-to-Treat Population ..........................................................................................68
9.3.2.
Safety Population........................................................................................................68
9.3.3.
Full Analysis Set (FAS)..............................................................................................68


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9.4.
Data Handling Conventions........................................................................................68
9.5.
Study Population.........................................................................................................68
9.5.1.
Patient Disposition......................................................................................................68
9.5.2.
Demographic and Baseline Characteristics ................................................................69
9.6.
Safety Variables and Analysis....................................................................................69
9.6.1.
Safety Variables..........................................................................................................69
9.6.2.
Safety Analysis ...........................................................................................................69
9.7.
Pharmacokinetic Analysis ..........................................................................................70
9.7.1.
Pharmacokinetic Variables and Endpoints.................................................................70
9.7.2.
Planned Method of Analysis.......................................................................................70
9.8.
Pharmacodynamic Analysis........................................................................................71
9.9.
Efficacy Analysis........................................................................................................71
9.10.
Planned Interim Analysis............................................................................................71
9.11.
Reporting Deviations from the Statistical Plan ..........................................................71
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................72
11.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................73
11.1.
Protocol Amendments and Protocol Deviations and Violations ................................73
11.1.1.
Protocol Amendments ................................................................................................73
11.1.2.
Protocol Deviations ....................................................................................................73
11.2.
Information to Study Personnel..................................................................................73
11.3.
Study Monitoring........................................................................................................74
11.4.
Audit and Inspection...................................................................................................74
12.
ETHICS ......................................................................................................................75
12.1.
Informed Consent/Assent ...........................................................................................75
12.2.
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards.........................................................................................................................75
12.3.
Confidentiality Regarding Study Patients ..................................................................75
12.4.
Declaration of the End of the Clinical Study..............................................................75
12.5.
Registration of the Clinical Study...............................................................................76
13.
DATA HANDLING, DATA QUALITY ASSURANCE, AND RECORD 
KEEPING ...................................................................................................................77
13.1.
Data Collection...........................................................................................................77
13.2.
Data Quality Assurance ..............................................................................................77


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13.3.
Archiving of Case Report Forms and Source Documents..........................................78
13.3.1.
Investigator Responsibilities.......................................................................................78
13.3.2.
Sponsor Responsibilities.............................................................................................78
14.
FINANCING AND INSURANCE.............................................................................79
15.
REPORTING AND PUBLICATION OF RESULTS................................................80
16.
REFERENCES ...........................................................................................................81
17.
SUMMARY OF CHANGES TO PROTOCOL .........................................................82
17.1.
Amendment 02 Dated 24 February 2016....................................................................82
17.2.
Amendment 01 Dated 11 January 2016......................................................................84


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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................38
Table 2:
Pharmacokinetic and Pharmacodynamic Assessments ..............................................40
Table 3:
Blood Volumes Required for Study Assessments......................................................50
Table 4:
Local Tolerability Assessment Scale..........................................................................61
Table 5:
Changes to the Protocol Amendment 02 ....................................................................83
Table 6:
Changes to the Protocol Amendment 01 ....................................................................85


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADA
anti-drug antibody
ADL
activities of daily living
ALT
alanine aminotransferase (SGPT)
ANC
absolute neutrophil count
AUCANC
area under the curve of absolute neutrophil count
AST
aspartate aminotransferase (SGOT)
AUC
area under the serum drug concentration by time curve
AUC0-12
area under the serum drug concentration by time curve from time 0 to 12 hours 
postdose
AUC0-∞
area under the serum concentration- time curve from time 0 to infinity
BLA
Biologic License Application
CDMS
clinical data management system 
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed plasma/serum drug concentration
CRF
case report form (refers to any media used to collect study data [ie, paper or 
electronic])
CTX
chemotherapy
DMC
Data Monitoring Committee 
DSN
duration of severe neutropenia
ECG
electrocardiography, electrocardiogram
EU
European Union
FAS
full analysis set
tbo-filgrastim
the investigational product in this study, has been approved as a biosimilar to 
filgrastim (Neupogen) in the EU, under the product names Tevagrastim, 
Ratiograstim and Biograstim (INN: filgrastim), and has the Teva product code 
XM02. It has been approved under the product name Granix (tbo-filgrastim) in 
the US via a BLA. To retain a consistent nomenclature throughout this 
protocol that distinguishes the investigational product from filgrastim 
(Neupogen), the investigational product is termed “tbo-filgrastim” throughout.
FDA
US Food and Drug Administration


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FN
febrile neutropenia
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INN
international nonproprietary name
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
LSO
local safety officer
MedDRA
Medical Dictionary for Regulatory Activities 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OTC
over-the-counter
PD
pharmacodynamics
PK
pharmacokinetics
QA
quality assurance
q.s
quantum sufficiat
r-metHuG-CSF
recombinant methionyl form of human granulocyte colony-stimulating factor
SC
subcutaneous
SD
standard deviation
SDS-PAGE
sodium dodecyl sulfate polyacrylamide gel electrophoresis
SOC
System Organ Class
SOP
standard operating procedure
t½
elimination half-life
tmax
time to maximum observed drug concentration
ULN
upper limit of the normal range
US
United States
USAN
United States approved name
WBC
white blood cell


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WHO
World Health Organization
WHO Drug
World Health Organization (WHO) drug dictionary


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1.
BACKGROUND INFORMATION
1.1.
Introduction 
Although cancer differs between adults and the pediatric population regarding incidence and cancer 
type, chemotherapy (CTX) has become a cornerstone of anti-cancer therapy in both populations. 
Intensive chemotherapeutic regimens have contributed to an increase in long-term disease-free 
survival in both adult and pediatric patients over the past decades. 
CTX can cause a decrease in the counts of neutrophils in the peripheral blood, a side effect termed 
“chemotherapy-induced neutropenia”. This important side effect occurs in more than 1 out of 
3 patients receiving CTX for cancer, and increases the chance of infection as well as the 
development of fever. In cases of severe CTX-induced neutropenia, life-threatening gastrointestinal 
and pulmonary infections may occur, as may sepsis. In addition to the increased risk of infections, 
CTX-induced neutropenia may also lead to chemotherapy cycle delay as well as chemotherapy dose 
reductions in subsequent cycles, thereby potentially affecting the efficacy outcomes intended from 
the CTX administration. 
In the pediatric population, CTX-induced neutropenia is the primary dose-limiting toxicity in 
patients receiving myleosuppressive chemotherapy (te Poele et al 2005). The definitions of 
neutropenia in children older than 1 year are the same as those for adults (Segel and Haltermann 
2008), and the risk factors are also consistent with those identified in the adult population.
Children receiving intensive CTX regimens have a 6 times greater chance of developing sepsis than 
those receiving more conservative and less intensive regimens (Mendes et al 2007). Many risk
factors have been identified for CTX-induced neutropenia and its serious medical complications, 
and several risk models have been developed (Lyman et al 2005). In pediatric patients, higher body 
temperature, prolonged neutropenia, a low monocyte count, and shock are predictive factors for the 
occurrence of bacteremia. 
Endogenous growth factors regulate the proliferation and differentiation of progenitor cells within 
the bone marrow and the release of mature neutrophils into the peripheral blood. They restore the 
number of neutrophils and keep it above the critical level (Holmes et al 2002). Recombinant 
granulocyte colony-stimulating factors (G-CSFs) have been developed and are part of standard
management for patients receiving intensive CTX at high risk of CTX-induced neutropenia. Current 
standard treatments for prevention of CTX-induced neutropenia, both in adult and pediatric 
populations, include recombinant human G-CSFs (filgrastim, Neupogen, Amgen [also biosimilars]), 
which have proven to add clinical benefit both as primary prophylaxis following the administration 
of high risk CTX when severe neutropenia is anticipated, as well as following retreatment with 
CTX after a previous cycle of CTX caused febrile neutropenia (FN; secondary prophylaxis). 
Filgrastim has also been shown to shorten the duration of severe CTX-induced neutropenia without 
fever (Goodwin et el 1998).
G-CSF, an endogenous growth factor, regulates the proliferation and differentiation of progenitor 
cells within the bone marrow and the release of mature neutrophils into the peripheral blood. G-CSF 
is a positive regulator of granulopoesis, acting at different stages of myeloid cell development. It
enhances the effector functions of normal mature neutrophils, including chemotaxis, phagocytosis,


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and oxidative metabolism. It exerts its effects via a high-affinity G-CSF-specific receptor 
mechanism, which accounts for its selective action as compared with many other cytokines. The 
natural human G-CSF is a glycoprotein composed of a single polypeptide chain of 174 or 177 
amino acids.
The bacterially synthesized non-glycosylated recombinant methionyl form of human G-CSF 
(r-metHuG-CSF) was approved by the United States (US) Food and Drug Administration (FDA) in 
1991 under the international nonproprietary name (INN) filgrastim. It is used for reducing the 
duration of neutropenia and the incidence of FN in patients undergoing myelosuppressive CTX for 
malignant diseases and for reducing the duration of neutropenia in patients undergoing 
myeloablative therapy followed by bone marrow transplantation and who are at risk of prolonged 
severe neutropenia. It is further used to mobilize peripheral blood stem cells as monotherapy or 
after myelosuppressive CTX. Finally it is indicated in long-term treatment of severe congenital, 
cyclical, or idiopathic neutropenia or neutropenia associated with advanced human 
immunodeficiency virus (HIV) infection.
Filgrastim was examined in a number of clinical trials investigating its efficacy in the treatment of 
neutropenia caused by cancer therapy. Administration of filgrastim was shown to increase absolute 
neutrophil counts (ANC) and to decrease the duration of neutropenia, the days of hospitalization,
and the number of infections. Therapy with filgrastim allowed the development of dose-intense 
regimens for the treatment of malignancies.
The present postmarketing study is designed to investigate the pharmacology and clinical effects of
tbo-filgrastim (the investigational product in this study which has been approved as a biosimilar to 
filgrastim [Neupogen] in the European Union [EU], under the product names Tevagrastim, 
Ratiograstim and Biograstim [INN: filgrastim], and has the Teva product code XM02 - it has been 
approved under the product name Granix (tbo-filgrastim) in the US via a Biologic License 
Application [BLA]. To retain a consistent nomenclature throughout this protocol that distinguishes 
the investigational product from filgrastim [Neupogen], the investigational product is termed 
“tbo-filgrastim” throughout) in children aged 1 month to <16 years with solid tumors without bone 
marrow involvement, who are scheduled to receive myelosuppressive CTX. The study was 
requested by the FDA to meet the requirements of the Pediatric Research Equity Act (21 U.S.C. 
355c) and section 505B (a) of the Federal Food, Drug, and Cosmetic Act. The study will be 
performed in conformity with the International Conference on Harmonisation (ICH) E6 guidance.
1.2.
Name and Description of Investigational Product
Tbo-filgrastim (also known as XM02) is a non-glycosylated r-metHuG-CSF expressed in 
Escherichia coli, and has a molecular weight of 18,798.98 Daltons. Tbo-filgrastim was developed 
as a biosimilar to filgrastim, the active substance in EU-sourced Neupogen.
Tbo-filgrastim was approved by the European Medicines Agency in September 2008, and is 
indicated for reducing the duration of neutropenia and the incidence of FN in patients treated with 
established cytotoxic CTX for malignancy (with the exception of chronic myeloid leukemia and 
myelodysplastic syndromes) and for the reduction in the duration of neutropenia in patients
undergoing myeloablative therapy followed by bone marrow transplantation considered to be at 
increased risk of prolonged severe neutropenia.


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Tbo-filgrastim was also approved by the FDA in August 2012, indicated for reduction in the 
duration of severe neutropenia (DSN) in adult patients with non-myeloid malignancies receiving 
myelosuppressive anti-cancer drugs associated with a clinically significant incidence of FN.
Tbo-filgrastim is administered by the subcutaneous (SC) or intravenous (IV) routes in the EU and 
SC in the US.
1.3.
Findings From Nonclinical and Clinical Studies
1.3.1.
Nonclinical Studies
The affinities of tbo-filgrastim and Neupogen for human G-CSF receptors were similar, and the 
binding was specific and dose-dependent. In 2 in vitro experiments with the cell line M-NFS-60, 
tbo-filgrastim and Neupogen induced half-maximum and maximum cell proliferation at similar 
concentrations.
Estimates of the relative potency in the cyclophosphamide-induced neutropenia model in mice 
indicated that tbo-filgrastim and Neupogen induce neutrophilia to a similar extent. The 
pharmacodynamic effects of tbo-filgrastim in monkeys after IV and SC administration were 
comparable. Tbo-filgrastim did not exhibit any tumor growth-promoting activity on human tumor 
cell lines and did not differ from Neupogen in that respect.
In safety pharmacology studies to evaluate the effects of tbo-filgrastim in vivo on the cardiovascular 
system in dogs, on the respiratory system in rats, and on the central nervous system in rats, no 
adverse effects were recorded after single SC administration of 3500 μg/kg, a dose 700-fold greater 
than the human dose.
Overall the kinetics of tbo-filgrastim in rat plasma remained unchanged following repeated SC 
dosing.
The pharmacokinetic profile of tbo-filgrastim was determined in the Cynomolgus monkey 
following single IV or SC injections. A slightly lower area under the drug concentration by time 
curve (AUC) following SC administration compared to IV administration was noted. The difference
was, however, not significant.
A single SC injection of 3500 μg/kg tbo-filgrastim to rats, 700-fold greater than the human dose, 
was not associated with any evidence of toxicity.
A multiple dose toxicity study in the rat using SC tbo-filgrastim revealed the following target 
organs: bone marrow, fore and hind limbs/paws and joints/tarsus, mesenteric lymph nodes, spleen,
and thymus. An increase in white blood cell (WBC) count concomitant with a change in 
lymphocyte count, extramedullary hematopoesis in the spleen, and myeloid hypercellularity in the 
bone marrow were observed, effects that are considered to be linked to the pharmacodynamic 
effects of tbo-filgrastim. Elevations in serum alkaline phosphatase were consistent with the 
increased bone formation observed. Osteoarthritis was observed in the tarsal joints. In the majority 
of samples analyzed, antibody titers produced against tbo-filgrastim were not detected.
Subcutaneous injections of tbo-filgrastim up to 125 μg/kg/day for 26 weeks to the monkey were 
generally well tolerated. Effects on hematology parameters, organ weight changes and macroscopic 
and microscopic findings were considered to reflect the pharmacological activity of tbo-filgrastim. 
Elevations in alkaline phosphatase were observed in high dose animals concomitant with an 


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increased bone turnover observed histopathologically. Bilateral bone cortical thickening and 
proliferative hyperostosis were noted in single animals at the high dose. In the vehicle group, 
occasional ventricular extrasystoles occurred in 2 animals and are known to occur spontaneously in 
the monkey. Test article action can thus be ruled out. Antibodies were present in all treated groups 
from the first determination in week 4, increased in week 12, and returned to lower levels in 
week 26. Exposure to the drug was slightly higher in males. A slight decrease in tbo-filgrastim 
plasma elimination over time was observed.
Local tolerance studies were performed in the rabbit. The results suggested that tbo-filgrastim can 
be safely administered to humans by the SC and IV routes. Erroneous maladministration is 
considered to cause no local intolerance.
The mutagenic potential of r-metHuG-CSF (filgrastim) was evaluated in vivo as well as in vitro. 
R-metHuG-CSF (filgrastim) was found to be not mutagenic. No additional mutagenicity tests were 
performed on tbo-filgrastim.
There is no evidence for carcinogenicity of any G-CSF product. Reproductive and developmental 
toxicity studies were not performed on XM02.
A 28-day study compared the immunogenicity of SC administered tbo-filgrastim and Neupogen in 
rats at doses of up to 125 μg/kg/day. The study drugs were generally well tolerated. During the 
treatment period known pharmacodynamic effects of tbo-filgrastim and Neupogen were seen (ie,
increased neutrophil counts, enlarged spleen and increases in spleen weights, and increased alkaline 
phosphatase activity). Most changes had subsided at the end of the treatment-free period. All 
changes observed were attributed to the direct and adaptive responses of the organism to the 
massive neutrophilic impulse given by G-CSF and are usually observed after G-CSF administration. 
The plasma concentrations revealed a dose-related exposure of the animals to tbo-filgrastim and 
Neupogen following SC injection. Toxicokinetic parameters were similar between sexes. The AUC 
values point to a slightly decreased clearance with time and, hence, a slight accumulation with time 
for the high-dose. All findings noted were caused by the pharmacodynamic effect of the test item. 
There were no differences in the safety profile with respect to pharmacodynamic effects or toxicity 
between tbo-filgrastim and Neupogen. The immunogenicity of tbo-filgrastim and Neupogen was 
comparable for all employed test assays. The percentage of samples positive for antibodies against 
both study drugs, the median and the maximal values per treatment group exhibited a time- and 
dose-dependent increase. Eleven percent of all samples were considered as antibody-positive. Based 
on the results of this trial, it can be concluded that the immunogenicity of tbo-filgrastim and
Neupogen is comparable.
1.3.2.
Clinical Studies
1.3.2.1.
Clinical Pharmacology and Efficacy Studies
Two single-blind, randomized, 2-way crossover, single-dose studies were performed in healthy 
male subjects and in healthy male and female subjects to compare the pharmacokinetic and 
pharmacodynamic profiles of tbo-filgrastim and EU-sourced Neupogen (Study XM02-01-LT and 
Study XM02-05-DE).
The first study compared the pharmacodynamic and pharmacokinetic parameters of tbo-filgrastim
and EU-sourced Neupogen in healthy male volunteers, when both treatments were administered SC 
at 5 or 10 µg/kg.


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Overall, the study results demonstrate that tbo-filgrastim is bioequivalent to the reference 
formulation filgrastim (Neupogen) with respect to the ANC time profile and the rate and the extent 
of absorption of G-CSF.
The second study compared the pharmacodynamic and pharmacokinetic parameters of 
tbo-filgrastim and EU-sourced Neupogen in healthy male and female volunteers, when both 
treatments were administered at 5 or 10 µg/kg by the IV or by the SC route.
Overall, the study results demonstrate that tbo-filgrastim is bioequivalent to the reference 
formulation filgrastim (EU-sourced Neupogen) with respect to the ANC time profile, the CD34+ 
count time profile, and the rate and the extent of absorption of G-CSF.
Five and 10 µg/kg treatments of tbo-filgrastim and EU-sourced Neupogen appear to be comparable 
with respect to the safety profile after single dosing by both the IV and the SC route.
Three multinational, multicenter, randomized, controlled Phase 3 studies were performed in patients 
with breast cancer (Study XM02-02-INT), small-cell or non-small-cell lung cancer 
(Study XM02-03-INT), and Non-Hodgkin Lymphoma (Study XM02-04-INT) receiving CTX.
In the study in breast cancer patients (Study XM02-02-INT), mean DSN in cycle 1 was 1.1 days for 
patients treated with tbo-filgrastim or filgrastim (EU-sourced Neupogen) and 3.9 days for patients 
receiving placebo. In the subsequent cycles, where all patients received tbo-filgrastim or filgrastim, 
mean DSN ranged from 0.5 to 0.7 days. For patients receiving tbo-filgrastim or filgrastim, the ANC 
values distinctly increased after start of treatment, reaching a maximum on day 3 and then 
decreased to a nadir on day 7. Thereafter, ANC values increased again, reaching a maximum on 
day 11. By the end of the cycle on day 21, mean values returned to values as observed on day 1.
The pharmacokinetic profiles of tbo-filgrastim and filgrastim (EU-sourced Neupogen) are similar,
and t½ values correspond to published data on filgrastim. No accumulation was observed for either 
filgrastim or tbo-filgrastim.
In summary, treatment with tbo-filgrastim was beneficial in ameliorating severe neutropenia in 
breast cancer patients receiving myelosuppressive CTX. The assay sensitivity with respect to the
DSN in cycle 1 for tbo-filgrastim versus placebo was confirmed. Tbo-filgrastim and filgrastim (EU-
sourced Neupogen) were significantly more effective than placebo in reducing the DSN in cycle 1 
of CTX in patients with breast cancer. Tbo-filgrastim was equally effective as filgrastim in reducing 
the DSN in cycle 1 of CTX in patients with breast cancer. Tbo-filgrastim and filgrastim had a 
similar effect on the incidence of FN and the time to ANC recovery. Finally, tbo-filgrastim and 
filgrastim had similar pharmacokinetic profiles.
The pharmacokinetic profiles of tbo-filgrastim and filgrastim (EU-sourced Neupogen) in patients 
with lung cancer (Study XM02-03-INT) were similar and correspond to data on filgrastim in the 
product information. No accumulation was observed for either filgrastim or tbo-filgrastim.
With regard to efficacy, which was investigated in an explorative manner in this safety study, there 
were no statistically significant differences between tbo-filgrastim and filgrastim with respect to the 
most important efficacy variables, DSN, and incidence of FN. 
It is concluded that tbo-filgrastim and filgrastim (EU-sourced Neupogen) have similar effects with 
regard to DSN and the incidence of FN in cycle 1 during CTX in patients with lung cancer, as 
demonstrated for the breast cancer patients.


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The pharmacokinetic profiles of tbo-filgrastim and filgrastim (EU-sourced Neupogen) in patients 
with Non-Hodgkin Lymphoma (Study XM02-04-INT) were similar and correspond to data on 
filgrastim in the product information. No accumulation was observed for either filgrastim or 
tbo-filgrastim. 
With regard to efficacy, which was only investigated in an explorative manner in this safety study, 
there were no statistically significant differences between tbo-filgrastim and filgrastim (EU-sourced 
Neupogen) in cycle 1 with respect to the DSN, the incidence of FN, ANC nadir, and the time to 
ANC recovery. It is concluded that tbo-filgrastim and filgrastim have similar effects with regard to 
the DSN, the incidence of FN, ANC nadir, and the time to ANC recovery during CTX in cycle 1.
1.3.2.2.
Clinical Safety Studies
Single SC injections and IV doses of 5 µg/kg and 10 µg/kg tbo-filgrastim and EU-sourced 
Neupogen have been studied in healthy male and female subjects (Study XM02-01-LT and 
Study XM02-05-DE).
Tbo-filgrastim and EU-sourced Neupogen were found to be safe and well tolerated in these studies. 
Headache and myalgia as well as skeletal pain in the first study and back pain in the second study 
were the most frequent adverse events related to the investigational product. These adverse events
were of mild to moderate intensity. Based on clinical observations, no difference was observed after 
a single SC or IV dose between the study drugs tbo-filgrastim and EU-sourced Neupogen with 
respect to their safety profile. Further, no difference was observed between the 5 and 10 µg/kg 
treatment groups.
Three multinational, multicenter, randomized, controlled Phase 3 studies were performed in patients 
with breast cancer (Study XM02-02-INT), small-cell or non-small-cell lung cancer 
(Study XM02-03-INT), and Non-Hodgkin Lymphoma (Study XM02-04-INT).
In 112 (32.2%) patients with breast cancer receiving CTX (Study XM02-02-INT), a total of 
294 treatment-emergent adverse events were considered as possibly study drug-related. Of these, 6
were considered severe in 6 (1.7%) patients. Two possibly study drug-related serious adverse events 
occurred in 2 (0.6%) patients: hypersensitivity (allergic reaction with bronchospasm) of severe 
intensity (tbo-filgrastim group) and syncope of severe intensity (placebo / tbo-filgrastim group in 
cycle 3). Three (3) patients (0.9%) discontinued the study due to a possibly study drug-related 
treatment-emergent adverse event.
The most commonly observed possibly drug-related treatment-emergent adverse events were bone 
pain (10.3%), asthenia (7.8%), myalgia (6.3%), and diarrhea (5.2%). In general, possibly drug-
related treatment-emergent adverse events occurred early in the study, ie, they were reported within 
15 days after study start and within the first 4 days of a cycle.
There were 6 cases of injection site reactions during the study (2 in the tbo-filgrastim group, 3 in the 
filgrastim group, and 1 in the placebo/tbo-filgrastim group).
In 50 (21.5%) patients with lung cancer receiving CTX (Study XM02-03-INT), a total of 
111 treatment-emergent adverse events were considered as possibly study drug-related. Of these, 
16 were considered severe in 11 (4.6%) patients. There were 4 possibly study drug-related serious 
adverse events in 3 (1.3%) patients, which were also considered related to CTX. Ten patients 
(4.2%) discontinued the study due to a possibly study drug-related treatment-emergent adverse 
event.


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The most commonly reported possibly drug-related treatment-emergent adverse events were 
myalgia (2.1%), back pain (2.1%), anemia (2.1%), and headache (2.1%). Possibly drug-related 
treatment-emergent adverse events were experienced early in the study, ie, they were reported 
within 20 days after study start, or within 6 days after start of a cycle. All cases of anemia possibly 
related to study drug were also reported to be possibly related to CTX.
There were 2 cases of injection site reactions during the study.
In summary, tbo-filgrastim was safe and well tolerated in patients with lung cancer receiving CTX.
In 63 (68.5%) patients with Non-Hodgkin Lymphoma receiving CTX (Study XM02-04-INT), a 
total of 310 treatment-emergent adverse events were considered possibly CTX-related. Of these, 
20 were considered severe in 13 (14.1%) patients. There were 16 possibly CTX-related serious 
adverse events in 12 (13.0%) patients, and 4 (4.3%) patients discontinued the study due to a 
possibly CTX-related treatment-emergent adverse event.
Most frequently reported possibly drug-related treatment-emergent adverse events (preferred term) 
were bone pain (9.8%) and arthralgia (4.3%). Possibly drug-related treatment-emergent adverse 
events were experienced early in the study, ie, they were reported within 20 days after study start, or 
within 4 days after start of a cycle.
There were 2 cases of injection site reactions during the study.
In summary, tbo-filgrastim was safe and tolerated in patients with Non-Hodgkin Lymphoma in the 
doses applied in this study.
Possibly drug-related serious adverse events observed in these studies were hypersensitivity 
(allergic reaction with bronchospasm), syncope of severe intensity, myocardial infarction, 
thrombocytopenia, and hyperuricemia.
The development of antibodies against tbo-filgrastim and EU-sourced Neupogen was investigated 
in the 3 cancer patient studies. Overall, the incidence of binding and neutralizing antibodies was 
low and similar between the treatment groups. Excluding implausible test results, only one 
borderline positive neutralizing test sample was found at the antibody follow-up visit (Ratiograstim 
Assessment Report 2008). In addition, it can be stated that no clinical signs of a possible 
neutralizing effect caused by antibodies were observed in any patient. There were no 
immunogenicity findings of clinical relevance which had “major consequences for efficacy and 
safety”.
According to the US prescribing information for tbo-filgrastim and the prescribing information for 
US Neupogen, the most common adverse drug reaction for filgrastim in cancer patients is bone pain 
(in 3.4% of treated patients). Potential serious adverse reactions are splenic rupture, acute 
respiratory distress syndrome, allergic reactions, alveolar hemorrhage and hemoptysis, and severe 
sickle cell crises in patients with sickle cell disease. The possibility that tbo-filgrastim acts as a 
growth factor for any tumor type cannot be excluded.
Very common (>10%) treatment-emergent adverse events observed during CTX (with or without 
filgrastim treatment) were nausea, vomiting, and γ-glutamyl-transpeptidase, lactate dehydrogenase, 
alkaline phosphatase, and uric acid increases, as well as chest pain and musculoskeletal pain. 
Common treatment-emergent adverse events (1%-10%) are alopecia, diarrhea, fatigue, anorexia, 
mucositis, headache, generalized weakness, cough, skin rash, throat pain, and constipation. Pain of 
unknown etiology is observed in <1% of patients, and vascular function disturbances are observed 


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in <0.1% of patients. Allergic reactions, deterioration of rheumatoid arthritis, pulmonary infiltrates, 
Sweet syndrome, cutaneous vasculitis, and urinary abnormalities are seen in <0.01% of patients.
Further adverse effects of G-CSFs are reported in healthy subjects undergoing peripheral stem cell 
mobilization (headache, musculoskeletal pain, leukocytosis, thrombocytopenia, increase in alkaline 
phosphatase and lactate dehydrogenase, severe allergic reactions, spleen disorder, increased levels 
of aspartate aminotransferase (AST), hyperuricemia and deterioration of arthritic symptoms, rupture 
of the spleen in very rare cases, in some cases lethal), in patients with severe chronic neutropenia 
(anemia, spleen enlargement, reduced glucose level, increase alkaline phosphatase and lactate 
dehydrogenase, hyperuricemia, pain of the musculoskeletal system, epistaxis, headache, diarrhea, 
thrombocytopenia, hepatomegalia, osteoporosis, alopecia, cutaneous vasculitis, pain at the injection 
site, rash, spleen disorder, hematuria, proteinuria) and in patients with HIV infection (pain of the 
musculoskeletal system, spleen disorder). For further information please refer to the prescribing 
information for tbo-filgrastim drug product.
1.3.3.
Postmarketing Safety Data
In the postmarketing experience in normal donors, in Europe, pulmonary adverse events 
(hemoptysis, pulmonary hemorrhage, lung infiltration, dyspnea, and hypoxia) have been reported. 
Transient cytogenic modifications have been observed in normal donors following G-CSF use. The 
significance of these changes in terms of the development of hematological malignancy is 
unknown. Long-term safety follow-up of donors is ongoing. A risk of promotion of a malignant 
myeloid clone can not be excluded.
In the latest Periodic Safety Update Report covering the period 01 April 2012 to 31 March 2013 it is 
concluded that the general benefit-risk ratio of filgrastim (parenteral formulations) shows an 
unchanged positive profile. Estimated post-approval cumulative exposure to Teva Group products 
containing filgrastim was 
. No new signals of concern were 
raised by data on either adults or children treated with filgrastim.
1.4.
Known and Potential Risks and Benefits to Human Subjects
The benefits of G-CSFs such as filgrastim are a reduction of the duration of neutropenia and the 
incidence of FN in patients treated with established cytotoxic CTX for malignancy (with the 
exception of chronic myeloid leukemia and myelodysplastic syndromes) and a reduction in the 
duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow 
transplantation.
The main adverse effect of G-CSFs such as filgrastim during short-term and long-term treatment is 
musculoskeletal pain. Hypersensitivity reactions have been reported rarely. Other adverse effects 
include splenic enlargement, thrombocytopenia, anemia, epistaxis, headache, diarrhea, and 
cutaneous vasculitis. There have been reports of pulmonary infiltrates leading to respiratory failure 
or acute respiratory distress syndrome, and rare reports of splenic rupture. Rises in lactate 
dehydrogenase, alkaline phosphatase, and uric acid, are usually mild to moderate, dose-dependent, 
and reversible (Ref.: Summary of Product Characteristics ratiograstim/tevagrastim, product 
information Neupogen).
Capillary leak syndrome has been reported after G-CSF administration and is characterized by 
hypotension, hypoalbuminemia, edema and hemoconcentration. Patients who develop symptoms of 


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capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, 
which may include a need for intensive care.
Additional information regarding risks and benefits to human patients may be found in the US 
prescribing information.
1.5.
Selection of Drugs and Dosages 
The dosage to be evaluated in this open-label study (ie, 5 μg/kg/day) is the only approved dosage 
for tbo-filgrastim in the US.
A more detailed description of study drug administration is presented in Section 5.1.
1.6.
Compliance Statement
This study will be conducted in full accordance with the ICH Good Clinical Practice (GCP) 
Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, 
Title 21 Code of Federal Regulations [21CFR] Parts 11, 50, 54, 56, 312, and 314, EU Directive 
20/EC and 28/EC). Any episode of noncompliance will be documented.
The investigators are responsible for performing the study in accordance with this protocol and the 
applicable GCP guidelines referenced above for collecting, recording, and reporting the data 
accurately and properly. Agreement of each investigator to conduct and administer this study in 
accordance with the protocol will be documented in separate study agreements with the sponsor and 
other forms as required by national authorities.
Each investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the study and must ensure that trained personnel are immediately available in the event of 
a medical emergency. Each investigator and the applicable study staff must be familiar with the 
background to, and requirements of, the study and with the properties of the study drug as described 
in the Investigator’s Brochure or prescribing information. 
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the study at that center and for contacts with study management, with 
the Independent Ethics Committee/Institutional Review Board (IEC/IRB), and with local 
authorities.
1.7.
Population To Be Studied
The study population will consist of subjects aged 1 month to <16 years with solid tumors without 
bone marrow involvement, who are scheduled to receive myelosuppressive CTX.
1.8.
Relevant Literature and Data
Relevant literature is cited above. Further literature and data may be found in the current 
Investigator’s Brochure.


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2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study
The purpose of the study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and 
efficacy of daily SC administration of 5 μg/kg tbo-filgrastim in infants, children and adolescents 
with solid tumors without bone marrow involvement.
2.2.
Study Objectives
The primary objective of the study is to assess the safety and tolerability of 5 µg/kg tbo-filgrastim in 
the pediatric population with solid tumors without bone marrow involvement.
The secondary objectives are to assess the pharmacokinetics using sparse sampling strategy, 
pharmacodynamics, efficacy, and immunogenicity of tbo-filgrastim in this patient population.


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3.
STUDY DESIGN
3.1.
General Design and Study Schema
This is a Phase 2, multicenter, open-label study to evaluate the safety, tolerability, 
pharmacokinetics, pharmacodynamics, efficacy, and immunogenicity of tbo-filgrastim at a dose of 
5 μg/kg/day in infants, children, and adolescents with solid tumors without bone marrow 
involvement scheduled to receive at least 1 cycle of CTX.
Three groups stratified by age (1 month to <2 years, 2 to <12 years, and 12 to <16 years) will be 
enrolled. Recruitment of subjects in the youngest age stratum (1 month to <2 years) will begin only 
once safety (from the start of study to CTX-day 21) and pharmacodynamic (from the start of study 
to day 15 [relative to first tbo-filgrastim administration]) results are available for a minimum of 
6 subjects in the middle age stratum group and have been reviewed by the Data Monitoring 
Committee (DMC) and no significant safety signals that prevent recruitment in the youngest age 
stratum have been detected.
Tbo-filgrastim administration will be started at approximately 24 hours (±3 hours) after the end of 
the last CTX treatment in the first week of this CTX cycle. Daily dosing with tbo-filgrastim should 
continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to 
2.0 × 109/L but not longer than on 14 consecutive days. 
Commercially available G-CSFs must not be administered during the treatment period of the study
or less than 6 weeks before inclusion. If a patient receives additional CTX treatments during the 
study follow-up period, G-CSFs may be administered at the discretion of the investigator.
The study will consist of 3 periods: screening period, treatment period, and follow-up period.
Screening period: Screening to confirm eligibility must be completed in 14 days or less prior to the 
initiation of CTX. 
Treatment period: Subjects will be treated for at least 1 cycle of CTX. The treatment period begins 
at the start of the first cycle of CTX administered under this protocol and ends at the end of this 
cycle (possibly immediately followed by further out-of-study CTX cycles). This period may last up 
to 3 weeks. The first dose of tbo-filgrastim will be administered 24 hours (±3 hours) after the end of 
last CTX in week 1 of this CTX cycle.
Follow-up period: The follow-up period includes collection of an immunogenicity sample at 
30 days and 3 months after last tbo-filgrastim study drug administration in the first cycle. 
During the conduct of the study, an independent DMC will review accumulating safety data on a 
regular basis to ensure the continuing safety of the study patients and study conduct issues. The 
maximum duration of the study for an individual patient (from screening period until the end of the
90-day follow-up period) will be approximately 18 weeks.
Patients who complete all scheduled visits will have final procedures and assessments performed at 
the end-of-study visit. Patients who withdraw from the study before completing the evaluation 
period will have end-of-study procedures and assessments performed at their final visit.


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3.2.
Primary and Secondary Measures and Endpoints
3.2.1.
Safety Measures and Endpoints
The safety of tbo-filgrastim will be assessed by evaluating the following:

adverse event reports throughout the study

clinical laboratory test results at screening and at the end-of-study visit

vital signs measurements (blood pressure, pulse rate, respiration rate, and body 
temperature) at screening, throughout the study treatment, and at the end-of-study visit

Electrocardiography (ECG) findings at screening, pre-dose, and 4 and 6 hours after the 
first tbo-filgrastim administration, and at the end-of-study visit

physical examination results at screening and at the end-of-study visit

concomitant medication usage throughout the study

local tolerability at the injection site at 1 hour (±30 min) after each study drug injection

spleen sonography assessments at screening, on day 4 of tbo-filgrastim treatment, at the 
end-of-study visit, and if the patient reports left upper abdominal and/or shoulder tip 
pain

ADA assessment prior to the first tbo-filgrastim administration, at the end-of-study visit,
and at 30 days and 3 months after the last tbo-filgrastim study drug treatment in the first 
cycle. 

survival at 90 day follow-up.
3.2.2.
Pharmacokinetic Measures and Endpoints
The pharmacokinetic measure for this study is serum concentration of tbo-filgrastim.
Blood samples for pharmacokinetics will be obtained on study day 1 within 1 hour prior to 
tbo-filgrastim administration (pre-dose) and at 2, 4, 6, 8, and 12 hours thereafter.
The allowed deviations from scheduled pharmacokinetic sampling time points (not recorded as 
protocol deviations) are ± 15 minutes. The actual time point is to be recorded.
Pharmacokinetic samples obtained in this study may also be used for assessment of drug binding to 
proteins, measurement of metabolites, or other purposes related to the absorption, distribution, 
metabolism, and excretion properties of the investigational product.
3.2.3.
Pharmacodynamic Measures and Endpoints
Blood samples for ANC measurement will be obtained within 1 hour prior to tbo-filgrastim 
administration on study day 1 and on days 5, 6, 7, 10, 12, and 15 (optional if day 15 coincides with 
CTX-day 21).
The pharmacodynamic measure for this study is ANC in blood (see Section 7.2.1).


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3.2.4.
Efficacy Measures and Endpoint
The efficacy measures for this study are axillary or external ear temperature and ANC in blood (see 
Section 8.1).
3.3.
Randomization and Blinding
This is a nonrandomized, open-label study.
3.4.
Study Drugs and Dosage
3.4.1.
Investigational Product and Dosage
3.4.1.1.
Tbo-filgrastim
Tbo-filgrastim is a biosimilar to filgrastim (Neupogen) in the EU, under the product names 
Tevagrastim, Ratiograstim and Biograstim (INN: filgrastim), and has the Teva product code XM02. 
It has been approved under the product name Granix (tbo-filgrastim) in the US via a BLA. It is a 
human G-CSF E. coli-derived protein consisting of 175 amino acids and has a molecular weight of 
approximately 18.8 kDa. The identity and sequence were confirmed by
 
and isoelectric focusing. In comparison with the 
corresponding human G-CSF, tbo-filgrastim is not glycosylated and additionally contains 
methionine in its NH2 terminal end. Its mechanism of action is as a G-CSF receptor (CD114) 
agonist.
3.4.1.2.
Formulation
The product is a sterile, clear, colorless, preservative-free solution containing tbo-filgrastim
(300 μg/mL), 
3.4.1.3.
Packaging, Labeling, Preparation, and Storage
Storage: Tbo-filgrastim will be supplied in vials containing 300 μg/mL. All drug product should be 
stored and maintained in a temperature-controlled environment according to the labeled storage 
conditions. Any temperature excursion outside of the labeled storage conditions should be 
communicated to Teva. Teva will evaluate each excursion and communicate the material 
disposition back to the notifying site. Protect from light. Avoid shaking. The solution should be 
visually inspected before use. Only clear solutions without particles should be used.
Packaging: The secondary packaging and labeling will be performed in accordance with Good 
Manufacturing Practice (GMP) and local regulatory requirements. The label text will be translated 
into the local language.
3.4.1.4.
Dose, Route of Administration, and Schedule
Tbo-filgrastim is to be administered subcutaneously. Patients will receive SC doses of 
tbo-filgrastim 5 μg/kg body weight daily; each daily dose, to be administered at the site, will be 
taken from a vial containing 300 µg/mL tbo-filgrastim. Injection of tbo-filgrastim is to be 
performed using a fine-graded syringe (gradations of 0.01 mL). After the syringe has been filled 


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with tbo-filgrastim, the needle is to be changed. Injection should be carried out using a new 
29G × ½ inch injection needle. The abdomen is the preferred location for injection.
The first dose of tbo-filgrastim will be administered not earlier than 24 hours (±3 hours) following 
the end of myelosuppressive CTX in week 1 of the cycle. Daily dosing with tbo-filgrastim should 
continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to 
2.0 × 109/L but not longer than on 14 consecutive days. A transient increase in neutrophil counts is 
typically seen 1 to 2 days after initiation of tbo-filgrastim therapy followed by the chemotherapy 
induced nadir.
3.4.2.
Other Study Drugs and Dosage
This is an uncontrolled study, ie, with no other study drug(s).
3.5.
Duration of Patient Participation
The study will consist of 3 periods: screening period, treatment period and follow-up period.
Screening period: Screening to confirm eligibility must be completed in 14 days or less prior to the 
initiation of CTX. 
Treatment period: Subjects will be treated for at least 1 cycle of CTX. The treatment period begins 
at the start of the first cycle of CTX administered under this protocol and ends at the end of this 
cycle (possibly immediately followed by further out of study-CTX cycles). This period may last up 
to 3 weeks. The first dose of tbo-filgrastim will be administered 24 hours (±3 hours) after the end of 
last CTX in week 1 of this CTX cycle.
Follow-up period: The follow-up period includes collection of an immunogenicity sample at 
30 days and 3 months following last study drug administration in the first cycle. 
The maximum duration of the study for an individual patient (from screening period until the end of 
the 90-day follow-up period) will be approximately 18 weeks.
3.6.
Stopping Rules and Discontinuation Criteria
3.6.1.
Early Discontinuation
Procedures will be completed within 5 days (±2 days) after the site has been informed of a patient’s 
decision to discontinue the study, or the investigator has decided to withdraw a patient. If a patient 
is withdrawn or chooses to withdraw, the same procedures described for the end of study evaluation 
will be offered to the patient. These include assessment of adverse events, vital signs, clinical 
laboratory tests, and immunogenicity test.
The reason for discontinuation will be documented in the source documents and captured on the 
case report form (CRF). The sponsor should be informed of all patients who withdraw or are 
withdrawn from the study.
Patients withdrawn from the study due to any adverse events will be followed up until the medical 
condition returns to baseline or is considered stable, at the discretion of the investigator, and will be 
recorded in the patient's source documents and in the CRF.


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Every effort should be made to understand and respect differences of opinion between the child and
his/her parents or legal representative regarding continuation in the study. Strong and definitive 
objections from the child should be respected.
3.6.2.
Criteria for Withdrawal
A patient may withdraw or be withdrawn from the study for the following reasons:
1. Patient’s parent(s)/legal representative(s) withdrew consent or strong objections to 
continuing in the study from the patient
2. Sponsor requested patient to be withdrawn
3. Request of primary care physician or investigator
4. Protocol violation/non-compliance
5. Loss to follow-up/failure to return
6. Adverse event (specify primary adverse event in the CRF)
7. Pregnancy
8. Death
3.6.3.
Replacement of Withdrawn Subjects
Patients who withdraw or are withdrawn after receiving study drug will not be replaced.
3.7.
Study Drug Supply and Accountability
3.7.1.
Study Drug Storage and Security
Tbo-filgrastim must be kept in a securely locked, substantially constructed cabinet or enclosure, 
with limited-access and should be stored and maintained in a temperature-controlled environment 
according to the labeled storage conditions.
All study drug will be stored in original containers until dispensed.
Only authorized personnel will have access to the study drug at the study centers.
The study site personnel at each site will be responsible for correct storage and handling of the 
study products.
3.7.2.
Study Drug Accountability
Study drug accountability records must be maintained at the site at all times. The identification 
number of the patient, the date, batch code, expiry date and quantity of study drug administered will 
be recorded.
During the study, used study medication should be discarded at the site according to local and 
national regulations. At study conclusion, all unused study drug vials can be destroyed only upon 
the sponsor's approval. Documented evidence of destruction should be made available to Teva.
The time and dosage of tbo-filgrastim administered will be recorded on the CRF.


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At the conclusion of the study, the investigator or designee will prepare an overall summary of all 
drug supplies received and used for the study. The investigator, pharmacist or drug administrator, 
and monitor must verify that no drug supplies remain in the investigator’s possession.
3.8.
Maintenance of Randomization and Blinding
This is an open-label study with no blinding.
3.9.
Source Data Recorded on the Case Report Form
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the CRF. Data may not be recorded directly onto the 
CRF and considered as source data unless the investigational center obtains written documentation 
from the sponsor, before the beginning of the study, indicating which data are permitted to be 
recorded directly onto the CRF. 
If data are processed from other institutions (eg, clinical laboratory, central image center, electronic 
diary data), the results will be sent to the investigational center, where they will be retained but not 
entered into the CRF unless otherwise noted in the protocol. These data may also be sent 
electronically to the sponsor (or organization performing data management) for direct entry into the 
clinical database (see Section 13.1). All data from other institutions will be available to the 
investigator(s).
The CRFs are filed in the sponsor’s central file.
3.10.
Time Schedule 
The study started in May 2015 and is expected to be completed in November 2016, with a duration 
of about 19 months.
Approximately 50 (minimum 30) patients from approximately 30 investigational centers are 
planned to be enrolled in the study. The study is planned to be conducted in Central and Eastern 
Europe, and the United States of America.
3.11.
Study Procedures
The study will consist of 3 periods: screening period, treatment period and follow-up period.
Screening period: Screening to confirm eligibility must be completed in 14 days or less prior to the 
initiation of CTX. 
Treatment period: Subjects will be treated for at least 1 cycle of CTX. The treatment period begins 
at the start of the first cycle of CTX administered under this protocol and ends at the end of this 
cycle (possibly immediately followed by further out-of-study CTX cycles). This period may last up 
to 3 weeks. The first dose of tbo-filgrastim will be administered 24 hours (±3 hours) after the end of 
last CTX in week 1 of this CTX cycle.
Follow-up period: The follow-up period includes collection of immunogenicity samples at 30 and 
90 days following last study drug administration in the first cycle. 
The maximum duration of the study for an individual patient (from screening period until the end of 
the 90-day follow-up period) will be approximately 18 weeks.


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Study procedures and assessments with their timing are summarized in Table 1, and
pharmacokinetic and pharmacodynamic assessments with their timing are summarized in Table 2.


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Table 1:
Study Procedures and Assessments
Screening
Treatment Period
Follow-up
CTX Cycle 1
CTX in Week 1
tbo-filgrastim administrationa
End of Study Visit
Procedure
  Days
CTX-D-14 
to CTX-D1
CTX-D1b
CTX-D2 to 
last CTX in 
Week 1
D1
(at 24 (± 3) hours 
after end of last 
CTX in Week 1)
D2 to D15
CTX-Day 21 (±2)
days; after PD 
period (and prior to 
next CTX cycle)
30 (±3) and 90 (±6) days 
from last tbo-filgrastim 
administration in CTX 
Cycle 1
Informed consent
X
Medical and psychiatric history
X
Medication history
X
Concomitant medicationc
X
X
X
X
X
X
Urine drug screen
X
Height and weight
X
Evaluation of eligibility 
X
Urine pregnancy testd
X
X
Physical examination
X
X
Vital signse
X
X
X
X
X
X
12-Lead ECGf
X
X
X
Serum chemistry
X
X
Hematology
X
X
Spleen sonographyg
X
X
X
Adverse event evaluationh
X
X
X
X
X
X
Xh
Chemotherapy administration
X
Xi
Xi
Tbo-filgrastim administration
Xj
Xa


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Screening
Treatment Period
Follow-up
CTX Cycle 1
CTX in Week 1
tbo-filgrastim administrationa
End of Study Visit
Procedure
  Days
CTX-D-14 
to CTX-D1
CTX-D1b
CTX-D2 to 
last CTX in 
Week 1
D1
(at 24 (± 3) hours 
after end of last 
CTX in Week 1)
D2 to D15
CTX-Day 21 (±2)
days; after PD 
period (and prior to 
next CTX cycle)
30 (±3) and 90 (±6) days 
from last tbo-filgrastim 
administration in CTX 
Cycle 1
Local tolerability at injection site
Xk
Xk
PK assessment
Xl
PD assessment (ANC) 
Xl
Xl
ADA assessment
X
X
X
Survival
X
a Daily dosing with tbo-filgrastim should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to 2.0 × 109/L but not 
longer than on 14 consecutive days. A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of tbo-filgrastim therapy followed by 
the chemotherapy induced nadir.
b All screening procedures can be performed on day 1 prior to start of CTX, as long as all laboratory/diagnostic results are available prior to start of CTX.
c Concomitant therapy or medication will be recorded after the ICF is signed, and throughout the study treatment period, and until 30-days from last 
tbo-filgrastim administration. 
d For female patients of child-bearing potential.
e Vital signs (blood pressure, pulse rate, respiration rate, and body temperature) should be obtained at each visit. Body temperature (axillary or external ear) is to 
be obtained twice daily (morning and evening) and recorded in the patient diary and CRF. 
f Repeat ECGs at pre-dose, 4 and 6 hours after first tbo-filgrastim in addition to screening and end of study assessment. A window of ±15 minutes is allowed.
g Spleen sonography to be conducted at screening, on day 4 of tbo-filgrastim treatment, at the end of study assessment, and if the patient reports left upper 
abdominal and/or shoulder tip pain.
h Adverse events will be recorded after the ICF is signed, throughout the study treatment period, and until 30 days from last tbo-filgrastim administration.
i Additional CTX treatments as per patient’s specific regimen.
j On day 1, ie, 24 hours (±3 hours) after the end of CTX in week 1. Administration of tbo-filgrastim is from day 1 but not longer than up to day 14.
k Tolerability assessment at 1 hour (±30 minutes) after the tbo-filgrastim administration
l See Table 2 for a detailed schedule of PK and PD assessments.
CTX-Dx=days of chemotherapy cycle 1; Dx=study days of tbo-filgrastim treatment period; ECG=electrocardiography; PD=pharmacodynamic.


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Table 2:
Pharmacokinetic and Pharmacodynamic Assessments
Procedure
Prior to tbo-
filgrastim dose 
on D1a
PK Assessments on day 1
Hours after first tbo-filgrastim dose 
PD Assessment
Day after first tbo-filgrastim dose
2
4
6
8
12
D5
D6
D7
D10
D12
D15
PK blood sample
X
X
X
X
X
X
PD blood sample for ANC
X
X
X
X
X
X
Xb
a Samples are to be obtained within 1 hour prior to the tbo-filgrastim dose.
b Optional if day 15 coincides with CTX-day 21 (ANC will be part of scheduled hematology sample on CTX-day 21).
PK=pharmacokinetic; PD=pharmacodynamic


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3.11.1.
Procedures for Screening and Enrollment 
A signed and dated informed consent form will be obtained from each parent/legal guardian, and 
a signed and dated assent form will be obtained from each patient before screening procedures 
commence, according to local IRB/IEC requirements. Evaluations obtained as part of routine 
medical care and performed during the screening period may be used in place of the 
study-specific evaluations. In case the results from the central laboratory will not be available on 
day 1 before start of CTX, the investigator may use test results from local laboratories in order to 
initiate CTX. In addition, disease-specific assessments performed within a specified time frame 
before informed consent may be used for the study. Parents/legal guardians will acknowledge 
and agree to the possible use of this information for the study by giving informed consent.
After informed consent is obtained, patients who are screened will be assigned an 8-digit 
permanent identification number such that all patients from each investigational center are given 
consecutive identification numbers in successive order of inclusion. The first 2 digits of the 
patient number will be the number assigned to the country where the investigational center is 
located, the next 3 digits will be the designated investigator center number, and the last 3 digits 
will be assigned at the investigator center (eg, if the number assigned to the country is 01, the 
3rd patient screened at center 5 would be given the number of 01005003).
A patient who is screened but not enrolled, eg, because entry criteria were not met or enrollment 
did not occur within the specified time, may be considered for screening again if, eg, there is a 
change in the patient’s medical background or a modification of study entry criteria. (Note: 
details of rescreening criteria and procedures are included in the Monitoring Plan for this study.)
The screening visit will take place not more than 14 days before the initiation of CTX. The 
following procedures will be performed at the screening visit:

obtain written informed consent before any other study-related procedures are 
performed

collect demographic data (sex, age, race, year of birth, and ethnicity)

review inclusion/exclusion criteria 

review medical and psychiatric history 

review medication history 

perform clinical laboratory tests

perform urine drug screen 

perform vital signs measurements (body temperature to be obtained twice daily 
[morning and evening] and recorded in the patient diary and CRF)

perform ECG

perform full physical examination (including height and weight)

perform urine pregnancy test (for female patients who have attained menarche)

perform spleen sonography


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
collect samples for ADA assessment

perform adverse event evaluation
3.11.2.
Procedures Before Study Drug Treatment
Patients who meet the inclusion/exclusion criteria at the screening visit will continue to the 
treatment period, which will begin at the start of the first cycle of CTX. Details of CTX
treatment will be recorded. 
The following procedures will be performed on day 1 of the CTX cycle (CTX-D1):

record concomitant medications

perform vital signs measurements (body temperature to be obtained twice daily 
[morning and evening] and recorded in the patient diary and CRF)

inquire about adverse events

administer CTX
The following procedures will be performed on day 2 of the CTX cycle (CTX-D2) to last CTX 
in week 1:

record concomitant medications

perform vital signs measurements (at each visit; body temperature to be obtained 
twice daily [morning and evening] and recorded in the patient diary and CRF)

inquire about adverse events

administer CTX (additional CTX treatments as per patient’s specific regimen)
A patient who is not enrolled in the study on the basis of results of baseline assessments (eg, 
because entry criteria were not met or enrollment did not occur within the specified time) may be 
considered for screening again if there is a change in the patient’s medical background, a 
modification of study entry criteria, or other relevant change. (Note: details of rescreening 
criteria and procedures are included in the Monitoring Plan for this study.)
Patients who continue to meet the inclusion/exclusion criteria will be enrolled into the study, and 
study drug will be dispensed.
3.11.3.
Procedures During Study Drug Treatment
3.11.3.1.
Day 1
The following procedures/assessments will be performed on day 1 of tbo-filgrastim 
administration (D1), ie, at 24 hours (±3 hours) after the end of the last CTX in week 1:

record concomitant medications

perform vital signs measurements

perform ECG (pre-dose and at 4 and 6 hours post-dose)

perform adverse event evaluation


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
administer tbo-filgrastim

assess local tolerability at injection site at 1 hour (±30 minutes) after the 
tbo-filgrastim administration

obtain blood sample for pharmacokinetic assessment (within 1 hour before 
tbo-filgrastim dose and at 2, 4, 6, 8 and 12 hours post-dose)

obtain pharmacodynamics blood sample for ANC assessment (within 1 hour before 
tbo-filgrastim dose)
3.11.3.2.
Day 2 to Day 15
The following procedures/assessments will be performed on days 2 to 15 of tbo-filgrastim 
administration:

record concomitant medications

perform vital signs measurements (at each visit; body temperature to be obtained 
twice daily [morning and evening] and recorded in the patient diary and CRF)

perform spleen sonography on day 4 (or if the patient reports left upper abdominal 
and/or shoulder tip pain)

perform adverse event evaluation

administer additional CTX (as per patient's specific regimen)

administer tbo-filgrastim not longer than up to day 14

assess local tolerability at injection site at 1 hour (±30 minutes) after the 
tbo-filgrastim administration

obtain pharmacodynamics blood sample for ANC assessment (on days 5, 6, 7, 10, 12, 
and 15 [optional if day 15 coincides with CTX-day 21])
3.11.4.
End-of-Study Visit (CTX-Day 21 [±2 days]; prior to next CTX cycle)
The following procedures/assessments will be performed at the end-of-study visit:

record concomitant medication

perform urine pregnancy test (for female patients who have attained menarche)

perform physical examination

perform vital signs measurements (body temperature to be obtained twice daily 
[morning and evening] and recorded in the patient diary and CRF)

perform ECG

perform clinical laboratory tests

perform spleen sonography

perform adverse event evaluation

collect sample for ADA assessment


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3.11.5.
Procedures After Study Drug Treatment
Patients who participate in the study in compliance with the protocol for the duration of at least 
1 cycle of CTX will be considered to have completed the study.
The following procedures/assessments will be performed at 30 (±3) and 90 (±6) days after the 
last tbo-filgrastim administration in CTX cycle 1:

collect samples for ADA assessment

assess survival

record concomitant medication (only until 30 days after the last tbo-filgrastim 
administration)

record adverse events (only until 30 days after the last tbo-filgrastim administration)
For patients who complete the study or withdraw prematurely, final evaluations will be 
performed at the end of treatment. Procedures for patients who withdraw prematurely from the 
study are described in Section 4.3.
Patients with ongoing adverse events or clinically significant abnormal laboratory test results (as 
interpreted by the investigator) will be monitored as described in Section 6.1.2 and Section 6.3, 
respectively. 
3.11.6.
Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the subject’s request or 
as deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded on the CRF as well as any other data obtained (eg, adverse events, concomitant
medications and treatments, and results from procedures or tests).


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
4.1.
Patient Inclusion Criteria
Patients may be included in the study only if they meet all of the following criteria:
a.
Male or female infants, children and adolescents aged 1 month to <16 years at the 
time of ICF signing.
b. Patients with solid tumors without bone marrow involvement (ie, non-myeloid 
neoplasms), who are scheduled to receive myelosuppressive CTX.
c.
Body weight ≥5 kg.
d. Written informed consent provided by parent(s)/legal representative(s) of the 
pediatric patient and patient’s assent if able to understand and/or follow study 
instructions alone or with parental assistance.
e.
Patients must have an initial diagnosis and histologic proof of their malignancy. 
Additionally, if the patients have a recurrence of their disease, clear radiographic or 
biopsy evidence is required within 4 weeks prior to study entry. 
f.
All enrolled subjects should have signed consent for a CTX regimen that is known to 
be myelotoxic, with counts expected to drop below the ANC of 0.5 × 109/L for at 
least 3 days. These regimens would include at least 1 of the following:

Etoposide

doxorubicin

ifosfamide

cyclophosphamide
g. ANC and platelet count: Patients must have an ANC >1 × 109/L and a platelet 
count >100 × 109/L to be eligible for therapy at the start of CTX.
h. Normal cardiac, renal, and hepatic function.
i.
All subjects must have a life expectancy of 12 weeks or more.
j.
Performance Status: Lansky performance score >60 (age 1 to <16 years).
k. Fertile and sexually active patients (male or female) must use highly reliable 
contraceptive measures (ie, 2 of the following: oral contraception, implants, 
injections, barrier contraception, and intrauterine device, or vasectomized/sterilized 
partners, or sexual abstinence). For purposes of this study, a fertile female patient is 
any female patient who has experienced menarche and who has not undergone tubal 
ligation. 
l.
Female patients who have attained menarche must have a negative urine pregnancy 
test at the screening visit.


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4.2.
Patient Exclusion Criteria
Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a.
Bone marrow involvement.
b. Active myelogenous leukemia or history of myelogenous leukemia.
c.
Previous treatment with colony-stimulating factors (G-CSF, granulocyte-macrophage 
colony-stimulating factor, Interleukin 11 [IL-11]) less than 6 weeks prior to study 
entry.
d. Known hypersensitivity to any component of this product.
e.
History of congenital neutropenia or cyclic neutropenia.
f.
Any illness or condition that in the opinion of the investigator may affect the safety of 
the patient or the evaluation of any study endpoint.
g. Pregnant or nursing female patients.
h.
Fertile patients who do not agree to use highly reliable contraceptive measures during 
the entire duration of the study.
i.
Prior bone marrow or stem cell transplant, or prior radiation to ≥25% of bone marrow 
(eg, whole pelvic radiation) for any reason, or any therapeutic radiation within the 
4 weeks prior to the first tbo-filgrastim dose.
j.
Ongoing active infection or history of infectious disease within 2 weeks prior to the 
screening visit.
k. Treatment with lithium at screening or planned during the study.
l.
[New criterion] Participation in an interventional clinical study within 30 days or 
5-half-lives of the investigational product before enrollment, whichever is longer.
4.3.
Withdrawal Criteria and Procedures
A patient may withdraw or be withdrawn from the study for the following reasons:
1. Patient’s parent(s)/legal representative(s) withdrew consent or strong objections to 
continuing in the study from the patient
2. Sponsor requested patient to be withdrawn
3. Request of primary care physician or investigator
4. Protocol violation/non-compliance
5. Loss to follow-up/failure to return
6. Adverse event (specify primary adverse event in the CRF)
7. Pregnancy
8. Death


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In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each patient is free to withdraw from the study at any time. Each investigator also 
has the right to withdraw a patient from the study in the event of intercurrent illness, adverse 
events, pregnancy (see Section 6.2 ), or other reasons concerning the health or well-being of the 
patient, or in the event of lack of cooperation. In addition, a patient may be withdrawn from the 
study as described in Sections 3.6 and 3.11.4.
Should a patient decide to withdraw after administration of the study drug, or should the 
investigator decide to withdraw the patient, all efforts will be made to complete and report all 
observations up to the time of withdrawal. A complete final evaluation at the time of the 
patient’s withdrawal should be made and an explanation given as to why the patient is 
withdrawing or being withdrawn from the study.
The reason for and date of withdrawal from the study must be recorded on the source 
documentation and transcribed onto the CRF. If a patient withdraws consent, every attempt will 
be made to determine the reason. If the reason for withdrawal is an adverse event or a clinically 
significant abnormal laboratory test result, monitoring will be continued at the discretion of the 
investigator (eg, until the event has resolved or stabilized, until the patient is referred to the care 
of a health care professional, or until a determination of a cause unrelated to the study drug or 
study procedure is made). The specific event or test result(s) must be recorded on the source 
documentation and transcribed onto the CRF. 
All evaluations should be performed according to the protocol for the end-of-study visit.
A patient who is enrolled but never treated with the study drug may be replaced with another 
qualified patient to ensure a minimum of 30 patients are evaluable for the primary endpoints.


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5.
TREATMENT OF PATIENTS
5.1.
Study Drugs Administered
Patients will receive SC doses of tbo-filgrastim 5 μg/kg body weight daily; each daily dose will 
be taken from a vial containing 300 µg/mL tbo-filgrastim.
The first dose of tbo-filgrastim should be administered not earlier than 24 hours (±3 hours) 
following the end of myelosuppressive CTX in week 1 of the cycle. Daily dosing with tbo-
filgrastim should continue until the expected neutrophil nadir is passed and the neutrophil count 
has recovered to 2.0 × 109/L but not longer than on 14 consecutive days. A transient increase in 
neutrophil counts is typically seen 1 to 2 days after initiation of tbo-filgrastim therapy followed 
by the chemotherapy induced nadir.
5.2.
Restrictions
Patients who violate any of the below restrictions may be excluded or dropped from the study at 
the discretion of the investigator(s).
5.2.1.
Concomitant Medications
During the treatment period of the study, the following medications are prohibited:
1. Commercially available G-CSF such as filgrastim, pegfilgrastim, or lenograstim or their 
biosimilars.
All other concomitant medications are allowed, at the investigator’s discretion.
5.2.2.
Prescription Medications
All prescription medications other than the prohibited medications mentioned in Section 5.2.1
are allowed. All medications taken should be detailed in the CRFs.
5.2.3.
Over-the-Counter Medications and Herbal Remedies
Any over-the-counter (OTC; non-prescription) medications, vitamins and herbal remedies taken 
should be detailed in the CRF.
5.2.4.
Contraceptive Measures
Fertile patients (male or female) must use highly reliable contraceptive measures (ie, 2 of the 
following: oral contraception, implants, injections, barrier contraception, and intrauterine device, 
or vasectomized/sterilized partners, or sexual abstinence). For purposes of this study, a fertile 
female patient is any female patient who has experienced menarche and who has not undergone 
tubal ligation.
Female patients who have attained menarche must have a negative pregnancy test at the 
screening visit. The patient and her parent(s) must be counseled on the importance of not 
becoming pregnant before or during the study treatment period.


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5.2.5.
Dietary
Investigators are encouraged to follow their local institutional guidelines, if any, to instruct their 
patients to follow a neutropenic diet.
5.2.6.
Tobacco
Tobacco use is not endorsed nor prohibited during the study.
5.2.7.
Exercise
There are no restrictions on exercise.
5.3.
Prior and Concomitant Therapy or Medication
Any prior or concomitant therapy, medication, or procedure a patient has had within 2 months
before study drug administration and up to the end of the study period, including follow-up, will 
be recorded on the CRF. Generic or trade name, indication, and dosage will be recorded. The 
sponsor will encode all therapy and medication according to the World Health Organization 
(WHO) drug dictionary (WHO Drug).
The following medications will not be allowed in CTX cycle 1 during this study:

Commercially available G-CSF such as filgrastim, pegfilgrastim, or lenograstim or 
their biosimilars
At each clinic visit after the screening visit, the investigator will ask patients and/or parents or 
legal representatives whether they have taken any medications (other than study drug), including 
OTC medications, vitamins, or herbal or nutritional supplements, since the previous visit.
5.4.
Procedures for Monitoring Patient Compliance
Each investigator will be responsible for monitoring patient compliance. A check of study drug 
compliance will be performed during each visit after the initial dispensation of study drug, and 
study drug accountability records will be completed. If the investigator or the sponsor determines 
that the patient is not in compliance with the study protocol, the investigator and the sponsor 
should determine whether the patient should be withdrawn. The IRB/EC should be notified.
5.5.
Total Blood Volume
Blood sampling may be performed using an indwelling catheter instead of multiple 
venipunctures to minimize patient discomfort, at the discretion of the investigator. In addition, 
the frequency and volume of blood samples has been set to the minimum that will allow the 
study objectives to be achieved.
According to EU guidelines (Ethical Considerations for Clinical Trials on Medicinal Products 
Conducted with the Paediatric Population: Recommendations of the ad hoc group for the 
development of implementing guidelines for Directive 2001/20/EC relating to good clinical 
practice in the conduct of clinical trials on medicinal products for human use), 2.4 mL blood 
per kg body weight drawn within 4 weeks is the acceptable limit. Patients participating in the 
study must have a minimum body weight of 5 kg, which results in an acceptable limit of


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approximately 12 mL blood within 4 weeks, especially when considering that the patients in this 
study are cancer patients scheduled to receive chemotherapy.
The total blood volumes required for the study assessments are described in Table 3 . Please 
refer to Sections 6.3, 6.7.4, 7.1.2, and 7.2.2 describing the study assessments for individual 
sample volumes for clinical laboratory, immunogenicity, pharmacokinetic, and 
pharmacodynamic evaluations, respectively.
Table 3:
Blood Volumes Required for Study Assessments
Assessment
Approximate Total Blood Volume
Pharmacokinetic
3.6 mL
Pharmacodynamic
3.5 mL
Clinical Laboratory 
2.0-4.0 mL
Immunogenicity 
2.4 mL
Total for Treatment Period
11.5-13.5 mL
Immunogenicity (30-day Follow-up)
1.2 mL
Immunogenicity (90-day Follow-up)
1.2 mL
Total for Study
13.9 – 15.9 mL


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6.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study staff by evaluating the following: 
reported adverse events, clinical laboratory test results, vital signs measurements, ECG findings, 
physical examination findings (including body weight and height measurements), concomitant 
medication usage, local tolerability at the injection site, spleen sonography, anti-drug antibodies 
assessment, and survival at 90 days follow-up.
6.1.
Adverse Events 
6.1.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product, regardless of whether it has a causal relationship with this treatment. 
In this study, any adverse event occurring after the ICF has been signed and throughout the study 
treatment period, and until 30 days from last tbo-filgrastim administration, should be recorded 
and reported as an adverse event.
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of the study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. A new condition or the worsening of a pre-existing 
condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that 
are present before study entry and do not worsen during the study will not be considered adverse 
events. 
Worsening of the disease under study should be recorded as an adverse event only if the 
presentation and/or outcome is more severe than would normally be expected from the normal 
course of the disease in a particular patient.
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions. (Note: a condition recorded as pre-existing that 
is intermittently symptomatic [eg, headache] and which occurs during the study
should be recorded as an adverse event.)

drug interactions

events occurring during diagnostic procedures or during any washout phase of the 
study

laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 


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event, or require medical treatment or further diagnostic work-up, or are considered 
by the investigator to be clinically significant. Note: Abnormal laboratory test results 
at the screening visit that preclude a patient from entering the study or receiving study 
treatment are not considered adverse events, but will be evaluated to monitor data
from patients who do not meet screening criteria. 

all events of possible drug-induced liver injury with hyperbilirubinemia (defined as 
AST or alanine aminotransferase [ALT] ≥3 times the upper limit of the normal range
[ULN], plus either bilirubin ≥2 times the ULN or international normalized ratio [INR]
>1.5) or Hy’s Law events require immediate study treatment cessation and reporting 
as a serious adverse event.
6.1.2.
Recording and Reporting Adverse Events
Adverse events will be recorded from the time a patient’s parent(s) or legal representative(s) has 
signed the ICF (and the adolescent patient has given informed assent) and throughout the study 
treatment period and until 30-days from the last tbo-filgrastim administration. They should be 
reviewed and updated at each subsequent visit within this period.
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the study drug. For serious adverse events, the Serious Adverse Event Form must 
also be completed and the serious adverse event must be reported immediately (see 
Section 6.1.5.3). All serious adverse events that occur after the study period must be reported by 
the investigator as described in Section 6.1.5.3.1.
At each contact with the patient, the investigator or designee must query the patient for adverse 
events by asking an open-ended question such as, “Have you had any unusual symptoms or 
medical problems since the last visit? If yes, please describe.” All reported or observed signs and 
symptoms will be recorded individually, except when considered manifestations of a medical 
condition or disease state. A precise diagnosis will be recorded whenever possible. When such a 
diagnosis is made, all related signs, symptoms, and any test findings will be recorded collectively 
as a single diagnosis on the CRF and, if it is a serious adverse event, on the Serious Adverse 
Event Form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to baseline, or until the patient is referred to the care of a health care 
professional, or until a determination of a cause unrelated to the study drug or study procedure is 
made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding study drug, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed onto the CRF. 
6.1.3.
Severity of an Adverse Event
The severity of each adverse event will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events, current version 4.03 (NCI CTCAE version 
4.03).


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Adverse events that are not included in the NCI CTCAE lists will be graded according to the 
NCI CTCAE general guideline for grades as follows:
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local intervention, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL), eg, preparing meals, shopping for 
groceries or clothes, using the telephone, managing money
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self care ADL, eg, bathing, 
dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to adverse event
6.1.4.
Relationship of an Adverse Event to the Study Drug
The relationship of an adverse event to the study drug is characterized as follows:
Term
Definition
Clarification
No 
reasonable 
possibility
(not related)
This category applies to adverse 
events which, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events, which, after careful 
medical consideration at the time 
they are evaluated, are judged to 
be unrelated to the study drug.
The relationship of an adverse event may be considered “no 
reasonable possibility” if it is clearly due to extraneous causes 
or if at least 2 of the following apply:

it does not follow a reasonable temporal sequence from the 
administration of the test drug.

it could readily have been produced by the patient’s clinical 
state, environmental or toxic factors, or other modes of 
therapy administered to the patient.

it does not follow a known pattern of response to the test 
drug. 

it does not reappear or worsen when the drug is 
re-administered.
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection 
with the test drug administration 
cannot be ruled out with certainty 
nor felt with a high degree of 
certainty to be related to the study 
drug.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following apply:

it follows a reasonable temporal sequence from 
administration of the drug.

it cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to 
the patient.

it disappears or decreases on cessation or reduction in dose. 
There are important exceptions when an adverse event does 
not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists.

it follows a known pattern of response to the test drug.


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6.1.5.
Serious Adverse Events
6.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

death

a life-threatening adverse event (ie, the patient was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
severe form, might have caused death

inpatient hospitalization or prolongation of existing hospitalization means that 
hospital inpatient admission and/or prolongation of hospital stay were required for 
treatment of an adverse event, or that they occurred as a consequence of the event. 
Hospitalizations scheduled for an elective procedure or for treatment of a pre-existing 
condition that has not worsened during participation in the study will not be 
considered serious adverse events. 

persistent or significant disability or incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions)

a congenital anomaly/birth defect

an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. Note: any suspected transmission of 
an infectious agent via a medicinal product is considered an important medical event.
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
6.1.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The reference safety information for this study is the Investigator’s 
Brochure. The sponsor’s Global Patient Safety & Pharmacovigilance Department will determine 
the expectedness for all serious adverse events.
6.1.5.3.
Reporting a Serious Adverse Event
6.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events (as described in Section 6.1.5.1) 
that occur during or after the study period (including the protocol-defined follow-up period), 
regardless of judged relationship to treatment with the study drug, must be reported to the 
sponsor by the investigator within 24 hours of when the investigator learns about it or, if the 


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event occurs on a weekend or national holiday, on the next working day. Completing the Serious 
Adverse Event Form and reporting the event must not be delayed, even if not all the information 
is available.
The Serious Adverse Event Form should be sent to the local safety officer (LSO) or other 
designated personnel (a contract research organization in a country without a Sponsor LSO) 
(contact information is in the Clinical Study Personnel Contact Information section); the LSO 
will forward the report to the sponsor’s Global Patient Safety & Pharmacovigilance Department.
The following information should be provided to record the event accurately and completely:

study number XM02-ONC-201

investigator and investigational center identification

patient number

patient initials

onset date and description of adverse event

investigator’s assessment of the relationship of the adverse event to the study drug 
(no reasonable possibility, reasonable possibility)
Additional information may include the following:

age and sex of patient

date of first dose of study drug

date and amount of last administered dose of study drug

action taken

outcome, if known

severity

concomitant therapy (including doses, routes, and regimens) and treatment of the 
event

pertinent laboratory or other diagnostic test data 

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death: 

cause of death (whether or not the death was related to study drug)

autopsy findings (if available)
The sponsor or its designee must ensure that the IC is also informed of the event, in accordance 
with local regulations.
For EU countries, the sponsor’s Global Patient Safety & Pharmacovigilance Department will 
distribute the Council for International Organizations of Medical Sciences (CIOMS) form/XML 


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file to the LSO for local submission to the regulatory authorities and IEC/IRBs and investigators 
according to regulations.
The LSO will be responsible for submission of the MedWatch form 3500/CIOMS form/XML 
file to the regulatory authorities. Serious adverse events should be reported by the sponsor to 
investigators. Investigators should report to their local IEC/IRB as dictated by their board’s 
policies and procedures.
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, but using the pregnancy form (see 
Section 6.2). 
6.1.5.3.2. Sponsor Responsibility
Serious adverse events of neutropenia are anticipated to occur in this study population with some 
frequency, independent of drug exposure. Therefore, the sponsor does not plan to report these 
events individually in an expedited manner. This provision has no impact on the investigator’s 
responsibility for reporting serious adverse events (see Section 6.1.5.3.1).
If a serious unexpected adverse event is believed to be related to the study drug or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of tbo-filgrastim and the appropriate regulatory authorities. 
In addition to notifying the investigators and regulatory authorities, other measures may be 
required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study

altering the process of informed consent by modifying the existing consent form and 
informing current study participants of new findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to tbo-filgrastim
6.1.6.
Protocol-Defined Adverse Events for Expedited Reporting
No protocol-defined adverse events for expedited reporting were identified for this study.
6.1.7.
Withdrawal Due to an Adverse Event
Any patient who experiences an adverse event may be withdrawn from the study at any time at 
the discretion of the investigator. If a patient is withdrawn wholly or in part because of an 
adverse event, both the adverse events page and termination page of the CRF will be completed 
at that time. 
The patient will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
investigator must inform the clinical project physician/clinical leader as soon as possible of all 
patients who are being considered for withdrawal due to adverse events. Additional reports must 
be provided when requested.


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If a patient is withdrawn from the study for multiple reasons that include adverse events, the 
termination page of the CRF should indicate that the withdrawal was related to an adverse event. 
An exception to this requirement will be the occurrence of an adverse event which in the opinion 
of the investigator is not severe enough to warrant discontinuation but which requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be need to take a prohibited medication, not the adverse event.
6.1.8.
Medical Emergencies
Medical emergencies must be reported to the individual identified in the clinical study personnel 
contact information section of this protocol.
Equipment, supplies, and properly skilled medical personnel must be accessible for an adverse 
event requiring immediate treatment. Any dose of study drug, whether taken intentionally or 
unintentionally, in excess of that prescribed must be immediately reported to the sponsor.
6.1.9.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure patient safety, the investigator or other physician in attendance must 
contact the individual identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study. Any 
departures from the protocol because of adverse events must be noted on the CRF and in source 
documents, along with the reason for such departures. 
6.2.
Pregnancy 
All pregnancies (pregnancies of females participating in the study and partners of males
participating in the study) that occur during the study, or within 30 days of completion of the 
study, are to be reported immediately to the individual identified in the Clinical Study Personnel 
Contact Information section of this protocol, and the investigator must provide the LSO with the 
pregnancy form. The process for reporting a pregnancy is the same as that for reporting a serious 
adverse event (see Section 6.1.5.3). 
Any patient becoming pregnant during the study will be withdrawn. All patients (or partners) 
who become pregnant will be monitored to the completion or termination of the pregnancy. If the 
pregnancy continues to term, the outcome (health of the infant up to 8 weeks of age), including 
spontaneous or voluntary termination, details of birth, and presence or absence of any birth 
defect, congenital abnormalities, or maternal and newborn complications, will be reported to the 
sponsor. Any complication of pregnancy will be reported as an adverse event or serious adverse 
event, as appropriate.
If the pregnancy does not continue to term, 1 of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.


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
For an elective abortion not due to developmental anomalies, report on the Pregnancy 
Form.
6.3.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be interpreted by the 
investigator as belonging to 1 of the following categories:

abnormal but not a clinically significant worsening

abnormal and a clinically significant worsening
A laboratory test result that has significantly worsened (according to medical judgment) from the 
baseline result will be recorded on the source documentation, transcribed onto the CRF as an 
adverse event, and monitored as described in Section 6.1.2. An adverse event includes a 
laboratory or diagnostic test abnormality (once confirmed by repeat testing) that results in the 
withdrawal of the patient from the study, the temporary or permanent cessation of treatment with 
study drug, or medical treatment or further diagnostic work-up.
Clinical laboratory tests (serum chemistry and hematology) will be performed at screening and at 
the end-of-study visit. Clinical laboratory tests will be performed using a central laboratory. In 
case the results from the central laboratory will not be available on day 1 before start of CTX, the 
investigator may use test results from local laboratories in order to initiate CTX. Specific 
laboratory tests to be performed are listed below.
6.3.1.
Serum Chemistry
The following serum chemistry tests will be performed:

ALT

AST

total bilirubin

direct bilirubin

indirect bilirubin

alkaline phosphatase

gamma-glutamyl transpeptidase 

lactic dehydrogenase 

glucose (non-fasting)

uric acid

creatinine

calcium

sodium

potassium 

phosphate


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6.3.2.
Hematology
The following hematology tests will be performed:

hemoglobin

hematocrit

red blood cell count 

platelet count

WBC absolute and relative counts

neutrophils

lymphocytes

eosinophils

monocytes

basophils
6.3.3.
Other Clinical Laboratory Tests
Other clinical laboratory tests will be performed to ensure the safety of the patients, but will not 
be used to assess the safety of the study drug.
6.3.3.1.
Human Chorionic Gonadotropin Tests 
Human chorionic gonadotropin urine tests will be performed for all female patients of 
childbearing potential at screening and if clinically indicated thereafter. Any patient who 
becomes pregnant during the study will be withdrawn. Procedures for reporting the pregnancy 
are provided in Section 6.2. 
6.4.
Vital Signs
In accordance with the schedule of study procedures shown in Table 1, vital signs will be 
measured at all visits. Vital signs include the following:

pulse rate

blood pressure

body temperature (axillary or external ear)

respiration rate
Body temperature is to be measured twice daily during the study, once in the morning and once 
in the evening, and recorded in a patient diary given to the patient or the 
parent(s)/representative(s) on day 1 of the CTX cycle. Additional measurements will be taken if 
the patient feels feverish. Body temperatures will be measured by the clinical staff for inpatients, 
and by the parent(s)/representative(s) for outpatients. Body temperature records will be 
transferred to the CRF. The efficacy variable is the incidence of FN which is defined as an 
axillary or external ear temperature >38.3°C or 2 consecutive readings >37.8°C for 2 hours (ie, 
2 consecutive readings at least 2 hours apart) and ANC<0.5 × 109/L.


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Before pulse and blood pressure are measured, the patient must be in a supine or seated position 
and resting for at least 5 minutes. (The same position and arm should be used each time vital 
signs are measured for a given patient.) For any abnormal vital sign finding, the measurement 
should be repeated as soon as possible. Any vital sign value that is judged by the investigator as 
a clinically significant change (worsening) from a baseline value will be considered an adverse 
event, recorded on the source documentation and transcribed onto the CRF, and monitored as 
described in Section 6.1.2.
6.5.
Electrocardiography
In accordance with the schedule of study procedures shown in Table 1, a 12-lead ECG will be 
conducted at screening, pre-dose, 4 and 6 hours post-dose on day 1 of tbo-filgrastim 
administration, and at the end-of-study visit. A qualified physician at the central diagnostic 
center identified in the front matter of this protocol will be responsible for interpreting the ECG. 
Any ECG finding that is judged by the investigator as a clinically significant change (worsening) 
compared with a baseline value will be considered an adverse event, recorded on the source 
documentation and transcribed onto the CRF, and monitored as described in Section 6.1.2.
6.6.
Physical Examinations
Physical examinations, including height (to be obtained at the screening visit only) and weight 
will be performed at screening and at the end-of-study visit. Any physical examination finding 
that is judged by the investigator as a clinically significant change (worsening) compared with a 
baseline value will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 6.1.2.
6.7.
Other Safety Measures and Variables
6.7.1.
Concomitant Medication
Concomitant therapy or medication will be recorded after the ICF is signed and throughout the 
study treatment period and until 30 days from last tbo-filgrastim administration. Details of 
prohibited medications are found in Section 5.3.
6.7.2.
Tolerability at the Injection Site
Local tolerability at the tbo-filgrastim injection site will be assessed at 1 hour (±30 minutes)
following tbo-filgrastim administration. The site will be assessed for the presence and severity of 
pain, erythema/redness, ecchymosis, and induration.
Severity of any reaction should be assessed as described in Table 4. At the discretion of the 
investigator, severe cases should be recorded as an adverse event.


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Table 4:
Local Tolerability Assessment Scale
Reaction
Severity grade
Parameter
Pain
0
Absent
1
Painful on touch
2
Painful when limb is moved
3
Spontaneously painful
Erythema/Redness
Record surface diameter in mm, if ≥5 mm
Ecchymosis
Record surface diameter in mm, if ≥5 mm
Induration
Record surface diameter in mm, if ≥5 mm
6.7.3.
Spleen Sonography
A sonographic examination of the spleen will be performed at screening, on day 4 of
tbo-filgrastim treatment, at the end-of-study visit, and if the patient reports left upper abdominal 
and/or shoulder tip pain.
Any abnormal findings or changes (worsening) compared to a baseline value assessed by the 
investigator as clinically significant should be recorded in the relevant CRF modules (eg, adverse 
event, medical history).
6.7.4.
Immunogenicity Assessment
In accordance with the schedule of study procedures shown in Table 1, blood will be drawn for 
the assessment of ADA at screening, at the end-of-study visit, and at 30 and 90 days after the last 
administration of tbo-filgrastim in CTX cycle 1.
Immunogenicity tests will require 1.2 mL blood samples (for 0.6 mL serum) collected in 
vacutainer tubes without anticoagulant. Details on sample processing are provided in 
Section 7.3.1.
At the follow-up visits, any use of filgrastim, pegfilgrastim, lenograstim, biosimilars or other 
investigational WBC growth factors since the end of study assessment will be documented.
6.7.5.
Survival at 90 Day Follow-up
Survival will be documented at 30 and 90 days after the last administration of tbo-filgrastim in 
CTX cycle 1.
6.8.
Methods and Timing of Assessing, Recording, and Analyzing Safety 
Data
Methods and timing of assessing safety data are discussed in Section 3.11. Procedures for 
recording safety data are discussed in Section 13.1 and methods of analyses are discussed in 
Section 9.6.2. 


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Furthermore, all adverse events will be reviewed on a periodic basis (eg, scheduled safety 
reviews for tbo-filgrastim) as interim/preliminary safety databases become available (see 
Section 6.1).
During the conduct of the study, an independent DMC will review accumulating safety data on a 
regular basis to ensure the continuing safety of the study patients and study conduct issues.
The DMC will be composed of independent physicians with expertise in the relevant therapeutic 
field and other relevant experts, such as a statistician. The DMC will receive safety data 
periodically. They will have the right to recommend discontinuation of the study for safety 
reasons.
DMC sessions can be open or closed. During open sessions, representatives of the sponsor and 
the Steering Committee may be present and information is provided and discussed. During 
closed sessions, the only participants are members of the DMC and the designated statistician (if 
approved to be present).
The DMC chairperson will communicate with the sponsor with regard to issues resulting from 
the conduct and clinical aspects of the study. The sponsor will work closely with the committee 
to provide the necessary data for review.
Recruitment of subjects in the youngest age stratum (1 month to <2 years) will begin only once 
safety (from the start of study to CTX-day 21) and pharmacodynamic (from the start of study to 
day 15 [relative to first tbo-filgrastim administration]) results are available for a minimum of 
6 subjects in the middle age stratum group and have been reviewed by the DMC and no 
significant safety signals that prevent recruitment in the youngest age stratum have been 
detected.


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7.
ASSESSMENT OF PHARMACOKINETICS, 
PHARMACODYNAMICS, AND IMMUNOGENICITY
7.1.
Pharmacokinetic Assessment
Samples will be analyzed for concentration of tbo-filgrastim using an appropriate validated 
method. Incurred sample reanalysis may be performed.
7.1.1.
Pharmacokinetic Variables
The pharmacokinetic variables are as follows:

maximum observed plasma/serum drug concentration (Cmax)

time to maximum observed drug concentration (tmax)

area under the serum drug concentration by time curve from time 0 to 12 hours 
postdose (AUC0–12)

area under the serum concentration-time curve from time 0 to infinity (AUC0–∞)

elimination half-life (t½)
7.1.2.
Blood Sampling and Handling
Blood samples (0.6 mL) will be collected via venipuncture or indwelling catheter (at the 
discretion of the investigator) within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8 and 
12 hours after the tbo-filgrastim dose on day 1, for serum concentration measurements of 
tbo-filgrastim.
The dates and times of study drug administration and the date and time of each pharmacokinetic 
sample will be recorded on the source documentation and transcribed onto the CRF. 
Samples will be collected into Vacutainer tubes containing no anticoagulant, inverted slowly 
6 to 8 times to mix the contents, and placed on water/ice (~4°C) for 45 to 90 minutes. Blood 
samples will be centrifuged (1500g, ~10 minutes, 2°C-6°C) between 4 minutes and 1.5 hours
after sampling. If a refrigerated centrifuge is not available, samples should be chilled before 
centrifugation. Other measures should be taken as appropriate to prevent samples from heating 
significantly during centrifugation. Separated serum will be transferred in approximately equal 
portions into 2 opaque, labeled, polypropylene tubes (sets A and B).
Sample labels should include the study number, patient number, period, scheduled sampling time 
point, set (A or B), and indication that they are pharmacokinetic samples. Serum samples will be 
stored at a temperature within the range of -60°C to -90°C in an upright position until they are 
shipped to the central laboratory or bioanalytical laboratory. Storage at -20°C is acceptable 
provided that the samples are shipped within 3 to 5 days from collection.
7.1.3.
Shipment of Samples
Serum samples for all patients will be shipped from the investigational center to the bioanalytical 
laboratory identified in the front matter of this protocol, where they will be stored until shipped 


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to the sponsor or its designee for analysis. Samples will be stored in an upright position at –60°C 
to –90°C until assayed. The bioanalytical laboratory will be notified before the shipment of the 
samples and will be sent the shipping information when the samples are shipped. An electronic 
file containing sample demographics (for example, Excel or .csv) will be emailed to the 
bioanalytical laboratory for each shipment. The same will be copied to the Teva Pharmaceuticals 
bioanalytical department representative responsible for the bioanalysis.
Set A samples will be transported, frozen, with a temperature data logger, with sufficient dry ice 
for 4 days, by next-day courier to the bioanalytical laboratory identified in the front matter of this 
protocol. 
Sample shipments should be sent no later in the week than Wednesday morning for next-day 
delivery. Samples are not to arrive on the weekend.
Samples will be analyzed using an appropriate validated method. Incurred sample reanalysis may 
be performed.
7.2.
Pharmacodynamic Variables
7.2.1.
Pharmacodynamic Variables
The pharmacodynamic variables are as follows:

incidence and duration of severe neutropenia (DSN, ANC<0.5 × 109/L)

area under the curve of ANC (AUCANC)

ANC nadir (measured in 109/L), which is the lowest ANC recorded

time to ANC nadir from the beginning of tbo-filgrastim administration up to the 
occurrence of the ANC nadir

time to ANC nadir from the beginning of CTX up to the occurrence of the ANC nadir

time to ANC recovery to ≥1.0 × 109/L, and time to ANC recovery to ≥2.0 × 109/L 
from ANC nadir 

time to ANC recovery to ≥1.0 × 109/L, and time to ANC recovery to ≥2.0 × 109/L 
from the beginning of tbo-filgrastim administration and from CTX-day 1
7.2.2.
Blood Sampling and Handling
Blood samples (0.5 mL) will be collected via venipuncture or indwelling catheter (at the 
discretion of the investigator) within 1 hour before the tbo-filgrastim dose on day 1, and on 
days 5, 6, 7, 10, 12, and 15 (optional if day 15 coincides with CTX-day 21).
The dates and times of study drug administration and the date and time of each 
pharmacodynamic sample will be recorded on the source documentation and transcribed onto the 
CRF. 
Pharmacodynamic assessments of ANC will require 0.5 mL blood at each time point.
All samples will be collected in ethylenediaminetetraacetic acid microtainer tubes bearing at a 
minimum, the patient’s number, study number, collection date and time (study hour).


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All pharmacodynamic samples for ANC will be sent to the local laboratory for evaluation. 
Details of blood sample handling, storage, and shipment will be described in a study specific 
clinical laboratory manual.
ANC will be determined using a standardized method at the local laboratories.
7.2.3.
Shipment of Samples
Not applicable.
7.3.
Immunogenicity Assessment
7.3.1.
Blood Sampling and Handling
Blood specimens (1.2 mL) will be collected via venipuncture or indwelling catheter (at the 
discretion of the investigator) for ADA analysis at screening (prior to the first tbo-filgrastim 
administration) at day 21±2 after the first tbo-filgrastim treatment, and at 30 and 90 days after 
the last tbo-filgrastim treatment.
Blood specimens will be collected into Vacutainer tubes containing no anticoagulant, and 
allowed to set at room temperature for between 45 and 90 minutes to allow for serum separation 
to occur. Samples will then be centrifuged (1500 g, ~10 minutes, 2-6°C). If a refrigerated 
centrifuge is not available, samples should be chilled before centrifugation. Other measures 
should be taken as appropriate to prevent samples from heating significantly during 
centrifugation. Separated serum will be transferred in approximately equal portions into 
2 opaque, labeled, polypropylene tubes (sets A and B).
Sample labels should include the study number, patient number, period, nominal collection time, 
set (A or B), and indication that they are ADA samples. Serum samples will be stored at a 
temperature within the range of -60 to -90°C in an upright position until they are shipped to the 
central laboratory or bioanalytical laboratory.
7.3.2.
Shipment and Analysis of Samples
Serum samples for all patients will be shipped from an investigational center to the central 
laboratory or bioanalytical laboratory identified in the front matter of this protocol, where they 
will be stored until shipped to the sponsor or its designee for analysis. Samples will be stored in 
an upright position at -60 to -90°C until assayed. The bioanalytical laboratory will be notified 
before the shipment of the samples and will be sent the shipping information when the samples 
are shipped. An electronic file containing sample demographics (for example, Excel or .csv) will 
be e-mailed to the bioanalytical laboratory for each shipment. The same will be cc’d to the Teva 
Pharmaceuticals bioanalytical department representative responsible for the bioanalysis. 
Set A samples will be transported, frozen, with a temperature data logger and with sufficient dry 
ice for 4 days, by next day courier to the bioanalytical laboratory identified in the front matter of 
this protocol. 
Set B samples will either be sent to the same laboratory as that for set A on a subsequent day by 
next day courier, or be retained at the investigational center until the study is completed and the 
clinical study report has been issued (unless shipment to another facility is requested by the 
sponsor). Instructions as to the disposition of the B samples will be provided by the sponsor.


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Sample shipments should be sent no later in the week than Wednesday morning for next day 
delivery. Samples are not to arrive on the weekend.
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the Teva Pharmaceuticals bioanalytical department 
representative responsible for the bioanalysis.


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8.
ASSESSMENT OF EFFICACY
8.1.
Efficacy Variable
The efficacy variable is the incidence of FN. FN is defined as an axillary or external ear 
temperature >38.3°C or 2 consecutive readings >37.8°C for 2 hours (ie, 2 consecutive readings at
least 2 hours apart) AND ANC<0.5 × 109/L.
The efficacy measure is axillary or external ear temperature.
8.2.
Methods and Timing of Assessing, Recording, and Analyzing 
Efficacy Data
Methods and timing of assessing efficacy data are discussed in Section 3.11. Procedures for 
recording efficacy data are discussed in Section 13.1, and methods of analyses are discussed in 
Section 9.9.


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9.
STATISTICS
9.1.
Study Design and Randomization
This is a non-comparative, open-label study.
9.2.
Sample Size and Power Considerations
The overall sample size of 50 (at least 6 in the infants group, 12 in the children group and 12 in 
the adolescents group) is not the result of a formal sample size calculation but was chosen for 
pragmatic reasons, taking into account the difficulty of recruiting subjects in the requested age 
classes for such a study, and is considered sufficient to allow exploratory analysis. Data will be 
evaluated using statistical approaches for exploratory data analyses.
9.3.
Analysis Sets/Populations 
9.3.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population will include all enrolled patients. A patient is considered 
enrolled when there is a record of patient eligibility. The set of enrolled patients includes all 
patients who were enrolled in the study, regardless of whether or not a patient took any study 
drug.
9.3.2.
Safety Population
The safety population will include all enrolled patients who receive at least 1 dose of study drug.
9.3.3.
Full Analysis Set (FAS)
The full analysis set (FAS) will include all patients in the ITT population who receive at least 
1 dose of study drug and have at least 1 postbaseline efficacy assessment. 
9.4.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the statistical analyses, 
ie, there is no plan to estimate missing data. For the calculation of pharmacodynamic parameters 
DSN and time to ANC recovery missing ANC values might be imputed. Details will be 
described in the Statistical Analysis Plan.
9.5.
Study Population
The set of enrolled patients (see Section 9.3) will be used for all study population summaries 
unless otherwise noted. Summaries will be presented for all patients.
9.5.1.
Patient Disposition
Data from patients screened, patients who are enrolled, patients enrolled but not treated, patients 
in the safety and full analysis sets, patients who complete the study, and patients who withdraw 
from the study will be summarized using descriptive statistics. Data from patients who withdraw 
from the study will also be summarized by reason for withdrawal using descriptive statistics.


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9.5.2.
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including medical history, prior medications, 
and ECG findings, will be summarized using descriptive statistics. For continuous variables, 
descriptive statistics (number [n], mean, standard deviation [SD], median, minimum, and 
maximum) will be provided. For categorical variables, patient counts and percentages will be 
provided. Categories for missing data will be presented if necessary.
9.6.
Safety Variables and Analysis
9.6.1.
Safety Variables
The safety analysis set (see Section 9.3) will be used for all safety analyses.
The overall safety and tolerability of tbo-filgrastim treatment will be assessed throughout the 
study by evaluating the following safety variables:

occurrence of adverse events throughout the study

clinical laboratory (serum chemistry, hematology, and urinalysis) test results at 
screening and at the end-of-study visit

vital signs (blood pressure and pulse) measurements at each visit

ECG findings at screening, pre-dose and 4 and 6 hours following the first 
tbo-filgrastim administration and at the end-of-study visit

physical examination findings, including body weight measurements, at screening 
and at the end-of-study visit

concomitant medication usage throughout the study

local tolerability at the injection site at 1 hour (±30 minutes) after each study drug 
injection

spleen sonography assessments at screening, on day 4 of tbo-filgrastim treatment, at 
the end-of-study visit and if the patient reports left upper abdominal and/or shoulder 
tip pain

ADA assessment prior to the first tbo-filgrastim administration, at the end-of-study 
visit, and at 30 and 90 days after last tbo-filgrastim study treatment

survival at 90 days follow-up
9.6.2.
Safety Analysis
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
(SOC) category for the analyses of safety. Summaries will be presented for all adverse events 
(overall and by severity), adverse events determined by the investigator to be related to study 
treatment (ie, reasonable possibility; see Section 6.1.4) (overall and by severity), serious adverse 
events, and adverse events causing withdrawal from the study. Summaries will be presented by 
treatment group and for all patients. Patient listings of serious adverse events and adverse events 


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leading to withdrawal will be presented. Adverse events will be tabulated by age group and 
across age groups using MedDRA SOCs and preferred terms.
Changes in laboratory and vital signs measurement data will be summarized descriptively. All 
values will be compared with prespecified boundaries to identify potentially clinically significant 
changes or values, and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with study drug.
For metrical safety variables mean, median, SD and minimum and maximum values will be 
calculated. Categorical variables will be statistically described by giving the number and percent 
of patients with the respective attribute. All statistical analyses will be broken down by age group 
and will also be displayed across age groups. Descriptive summaries of serious adverse events, 
patient withdrawals due to adverse events, and potentially clinically significant abnormal values 
(clinical laboratory or vital signs) based on predefined criteria will also be provided.
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the clinical study report. 
9.7.
Pharmacokinetic Analysis 
9.7.1.
Pharmacokinetic Variables and Endpoints
The pharmacokinetic variables and endpoints for this study are as follows: 

Cmax

tmax

AUC0-12

AUC0-inf

t1/2
9.7.2.
Planned Method of Analysis
Pharmacokinetic parameters derived for serum concentrations will be individually listed and 
summarized for each age group (number of subjects, mean, SD, geometric mean [for AUCs and 
Cmax], coefficient of variation, minimum, median, and maximum). 
Serum concentration data will similarly be individually listed and summarized using descriptive 
statistics by nominal time point.
Serum concentration-time profiles for each subject will be presented graphically. Mean serum 
concentration-time profiles will be presented by age group. 
The initial analysis of the pharmacokinetic data will be performed using noncompartmental 
analysis methods. Due to the sparse sampling design of this study, it is possible that population 
compartmental pharmacokinetic analysis using the computer program NONMEM will be 
performed to provide a more robust estimation of the pharmacokinetic parameters and to 
correlate the pediatric pharmacokinetic data with the pharmacodynamic endpoints collected in 


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this study. In addition, available pharmacokinetic/pharmacodynamic data from adult studies with 
more extensive sampling may be added to the population pharmacokinetics model in order to 
support the pharmacokinetics modeling effort. If this analysis is performed, it will be reported 
separately.
9.8.
Pharmacodynamic Analysis
For continuous pharmacodynamic variables mean, median, SD and minimum and maximum 
values will be calculated. Categorical variables will be statistically described by giving the 
number and percent of patients with the respective attribute. All statistical analyses will be 
broken down by age group and will also be displayed across age groups. For pharmacodynamic
metrics (ANCAUC, ANC nadir, time to ANC recovery) appropriate regression models will be 
estimated to scrutinize the influence of age and possible other baseline characteristics (eg, sex, 
type of cancer, type of CTX) on the respective metric.
9.9.
Efficacy Analysis
The incidence of febrile neutropenia will be summarized by a frequency table along with 95% 
confidence intervals for the incidence rate, by age group and across age groups.
9.10.
Planned Interim Analysis
No interim analysis is planned for this study.
9.11.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the complete statistical plan, the clinical study report, or any 
combination of these, as appropriate.


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10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The medical experts, study monitors, auditors, IEC/IRB, and health authority inspectors (or their 
agents) will be given direct access to source data and documentation (eg, medical charts/records, 
laboratory test results, printouts, videotapes) for source data verification, provided that patient 
confidentiality is maintained in accordance with local requirements.
Each investigator must maintain the original records (ie, source documents) of each patient’s 
data at all times. Examples of source documents are hospital records, office visit records, 
examining physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, 
drug inventory, study drug label records, diary data, protocol required worksheets, and CRFs that 
are used as the source (see Section 3.9).
Each investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient. All study-related documents must be kept until 
notification by the sponsor.


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11.
QUALITY CONTROL AND QUALITY ASSURANCE
11.1.
Protocol Amendments and Protocol Deviations and Violations
11.1.1.
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB, except when necessary to 
address immediate safety concerns to the patients or when the change involves only logistics or 
administration. The principal investigator and the sponsor will sign the protocol amendment. 
11.1.2.
Protocol Deviations
Any significant deviation from the protocol will be considered a protocol violation. Protocol 
violations include nonadherence on the part of the patient, the investigator, or the sponsor to 
protocol-specific inclusion/exclusion criteria, primary objective variable criteria, or GCP 
guidelines; noncompliance to study drug administration; use of prohibited medications; or any 
other deviations that may have an impact on the processes put in place for the care and safety of 
the patients. Protocol violations will be identified and recorded by investigational center
personnel on the CRF. All protocol violations will be reported to the responsible IRB/IEC, as 
required.
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documented approval 
from the medical representative. The decision will be based on ensuring the safety of the patient 
and preserving the integrity of the study. 
Deviations from the inclusion/exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
eligibility criteria was entered into a study, they must immediately inform the sponsor of the 
protocol violation. If such a patient has already completed the study or has withdrawn early, no 
action will be taken but the violation will be recorded.
11.2.
Information to Study Personnel
Each investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new staff become involved). Each investigator must 
assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the 
investigational center authorization form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary. Each 
investigator is responsible for notifying Teva GCQA of any clinical product complaint.
The study monitor is responsible for explaining the protocol to all study staff, including each
investigator, and for ensuring they comply with the protocol. Additional information will be 
made available during the study when new staff become involved in the study and as otherwise 
agreed upon with either the investigator or the study monitor.


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11.3.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable standard operating procedures (SOPs), the protocol, and other written 
instructions and regulatory guidelines.
The study monitor is the primary association between the sponsor and each investigator. The 
main responsibilities of the study monitors are to visit each investigator before, during, and after 
the study to ensure adherence to the protocol, that all data are correctly and completely recorded 
and reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IRB/IEC approvals.
The study monitors will contact each investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (CRFs and other pertinent source data records, to include specific electronic 
source documentation [see Section 3.9]) relating to the study to verify adherence to the protocol 
and to ensure the completeness, consistency, and accuracy of the data being recorded. If 
electronic CRFs are used for the study, the study monitor will indicate verification by 
electronically applying source document verification flags to the CRF and will ensure that all 
required electronic signatures are being implemented accordingly.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. Each investigator and 
assisting staff must agree to cooperate with the study monitor to resolve any problems, errors, or 
possible misunderstandings concerning the findings detected in the course of these monitoring 
visits and/or provided in follow-up written communication.
11.4.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP, and applicable regulatory requirements. The sponsor quality assurance
(QA) unit, independent of the Clinical Research Department, is responsible for determining the 
need for (and timing of) an investigational center audit.
Each investigator must accept that regulatory authorities and sponsor representatives may 
conduct inspections to verify compliance with GCP guidelines.


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12.
ETHICS
12.1.
Informed Consent/Assent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient and parent or other legally acceptable representative of all pertinent aspects of the study 
including the written information approved by the IRB/IEC. A signed and dated informed 
consent/assent form will be obtained from each parent/guardian and a signed and dated assent 
form will be obtained from each applicable minor patient before any study-specific procedures or 
assessments are done and after the aims, methods, anticipated benefits, and potential hazards are 
explained; according to local IRB/IEC requirements. Before the patient’s participation in the 
study, the written assent form will be signed and personally dated by the parent/guardian. Each 
investigator will keep the original consent/assent forms and copies will be given to the 
patients/parent/guardian. It will also be explained to the patient and parent/guardian that the 
patient is free to refuse entry into the study and free to withdraw from the study at any time 
without prejudice to future treatment.
Written and/or oral information about the study in a language understandable by the 
parent/guardian will be given to all parents/guardians with ample time for their consent/assent.
12.2.
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards
Before this study starts, the protocol will be submitted to the national/local health authorities and 
to each IEC/IRB for review. As required, the study will not start at a given investigational center
before the IEC/IRB and health authority (where applicable) for the center give written approval 
or a favorable opinion.
12.3.
Confidentiality Regarding Study Patients
Each investigator must assure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification code (eg, initials and identification number).
Personal medical information may be reviewed for the purpose of patient safety and/or verifying 
data in the source and transcribed onto the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, the QA unit, and/or regulatory 
authorities. Personal medical information will always be treated as confidential.
12.4.
Declaration of the End of the Clinical Study
For clinical investigational centers located in the EU, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); 
for other countries, local regulations will be followed.


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12.5.
Registration of the Clinical Study
This clinical study will be registered on clinical trial registry websites according to Teva standard 
procedures.


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13.
DATA HANDLING, DATA QUALITY ASSURANCE, AND 
RECORD KEEPING
13.1.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21 CFR part 11. The CDMS will be fully validated to ensure 
that it meets the scientific, regulatory, and logistical requirements of the study before it is used to 
capture data from this study. Before using the CDMS, all users will receive training on the 
system and any study-specific training. After they are trained, users will be provided with 
individual system access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient screened according to the data source. 
Patient identity should not be discernible from the data provided on the CRF. Data will be 
verified using the data source by the study monitor, and reviewed for consistency by Data 
Management using both automated logical checks and manual review. All data collected will be 
approved by the investigator at the investigational center. This approval acknowledges the 
investigator’s review and acceptance of the data as being complete and accurate. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data), the results will be sent to the investigational center, where 
they will be retained but not entered into the CRF unless otherwise specified in the protocol. 
These data may also be sent electronically to the sponsor (or organization performing data 
management) for direct entry into the clinical database (see Section 3.9). Laboratory test results 
will not be entered into the CRF unless otherwise noted in the protocol. All data from other 
sources will be available to the investigator(s).
For patients who enter a study but do not meet screening criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered into the CRF. 
13.2.
Data Quality Assurance
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Data handling, including data QA, will comply with 
international regulatory guidelines, including ICH GCP guidelines. Data management and 
control processes specific to this study, along with all steps and actions taken regarding data 
management and data QA, will be described in a data-management plan.
CRFs received will be processed and reviewed for completeness, consistency, and the presence 
of mandatory values. Applicable terms will be coded according to the coding conventions for 
this study. Logical checks will be implemented to ensure data quality and accuracy. Any 
necessary changes will be made in the clinical database, and data review and validation 
procedures will be repeated as needed. Data from external sources will be compared with the 
information available in the CDMS. Discrepancies found will be queried.


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Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes.
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate.
13.3.
Archiving of Case Report Forms and Source Documents 
13.3.1.
Investigator Responsibilities
All records related to the study (ie, source data, source documents, CRFs [see Section 3.9], data 
results from other sources [see Section 13.1], copies of protocols and protocol amendments, drug 
accountability forms, correspondence, patient identification lists, signed informed consent forms, 
and other essential documents) must be retained until the sponsor notifies the institution, in 
writing, that records may be destroyed. 
If the sponsor has not provided written notification of records destruction after 15 years from 
study completion (or earlier in the event of an institution closing), and the institution determines
the study record retention is unduly burdensome, the institution may submit a written request to 
the sponsor at least 60 days before the planned disposition of the study records. No study 
document or image (eg, scan, radiograph, ECG tracing) should be destroyed without prior 
written agreement between the sponsor and each investigator. Should an investigator wish to 
assign the study records to another party or move them to another location, advance written 
notice will be given to the sponsor.
13.3.2.
Sponsor Responsibilities
The sponsor will be responsible for the processing and quality control of the data. Data 
management and filing will be carried out as described in the sponsor’s SOPs for clinical studies.
If data management and filing of documents for this study are delegated to a contract 
organization, these functions will be carried out as described in the SOPs for clinical studies at 
that organization. These SOPs will be reviewed by the sponsor before the start of data 
management and filing activities. The original CRFs will be archived by the sponsor.
Center-specific CRFs will be provided to the respective study centers for archiving.


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14.
FINANCING AND INSURANCE
A separate financial agreement will be made between the principal investigator and the sponsor 
before the study drug is delivered.
This clinical study is insured in accordance with the corresponding local legal provisions. 
The policy coverage is subject to the full policy terms, conditions, extensions, and exclusions.
Excluded from the insurance cover are, inter alia, damages to health and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study.
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor.


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15.
REPORTING AND PUBLICATION OF RESULTS
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements for registration and posting of 
results. 
The sponsor is responsible for preparing a clinical study report, in cooperation with the 
coordinating investigator. The final report is signed by the sponsor and, if applicable, by the 
coordinating investigator.
When the sponsor generates reports from the data collected in this study for presentation to 
regulatory authorities, drafts may be circulated to the coordinating investigator for comments and 
suggestions. An endorsement of the final report will be sought from the coordinating 
investigator.
All unpublished information given to each investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. The primary 
publication from this study will report the results of the study in accordance with the current 
“Uniform Requirements for Manuscripts Submitted to Biomedical Journals” as established by 
the International Committee of Medical Journal Editors (www.ICMJE.org). Authorship will be 
restricted to parties who have editorial or conceptual input to protocol design, collection of data 
and/or analysis, interpretation of data, and manuscript preparation. The publications committee 
established by the sponsor will oversee this process. Additional publications may follow. Policies 
regarding the publication of the study results are defined in the financial agreement. 
No patent application(s) based on the results of the study may be made by each investigator nor 
may assistance be given to any third party to make such an application without the written 
authorization of the sponsor.


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16.
REFERENCES
Assessment Report for Ratiograstim, EMEA/502481/2008.
Goodwin JE, Kopecky KJ, Head DR, Willman CL, Leith CP, Hynes HE, et al. A double-blind 
placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with 
previously untreated acute myeloid leukemia: a Southwest oncology group study (9031).Blood 
1998;91(10):3607-15.
Holmes FA, Jones SE, O’Shaughnessy J, Vukelja1 S, George1 T, Savin M, et al. Comparable 
efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in 
chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast 
cancer. Ann Oncol 2002;13:903-9.
Lyman GH, Lyman CH, Agboola O, for the ANC Study Group. Risk models for predicting 
chemotherapy-induced neutropenia. The Oncologist 2005;10:427-37.
Mendes AVA, Sapolnik R, Mendonça N. New guidelines for the clinical management of febrile 
neutropenia and sepsis in pediatric oncology patients. J Pediatr (Rio J) 2007;83(2 Suppl):S54-63.
Segel GB, Haltermann JS. Neutropenia in pediatric practice. Pediatr Rev 2008;29(1):12-24.
te Poele EM, Kamps WA, Tamminga RYJ, Leeuw JA, Postma A, de Bont ESJM. Pegfilgrastim 
in pediatric cancer patients. J Pediatr Hematol Oncol 2005;27:627-9.


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17.
SUMMARY OF CHANGES TO PROTOCOL
17.1.
Amendment 02 Dated 24 February 2016
The primary reason for this amendment is to delete the requirement of administering at least 
5 daily doses of tbo-filgrastim in the CTX cycle. This is in response to the FDA comment that 
the instruction to administer at least 5 days of tbo-filgrastim is not consistent with labeling or the 
current standard of care. The proposed protocol change was intended to provide advice and 
clarify for the investigators “when the expected nadir is passed”, since a transient increase in 
neutrophil counts is typically seen 1 to 2 days after initiation of tbo-filgrastim therapy, but this 
does not imply that the nadir has passed.
The tbo-filgrastim dosing schedule has been amended to clarify that the dosing schedule 
indicating that a transient increase in neutrophil counts is typically seen 1 to 2 days after 
initiation of tbo-filgrastim therapy followed by the chemotherapy induced nadir”.
Table 1 (Study Procedures and Assessments) has been revised to reflect changes described 
below.
The revisions listed below have been made to the protocol (and protocol synopsis, as 
appropriate) and are considered substantial by the Teva Authorized Representative.


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Table 5:
Changes to the Protocol Amendment 02
Original text with changes shown
New wording
Reason/Justification for change
3.0 STUDY DESIGN
3.1. General Design and Study Schema (other sections affected by this change: Section 3.4.1.4., Section 5.1., and Clinical Study Synopsis)
Daily dosing with tbo-filgrastim At least 5 daily 
doses of tbo filgrastim will be administered in this 
cycle and administration should continue until the 
expected neutrophil nadir is passed and the 
neutrophil count has recovered to 2.0 × 109/L, but 
not longer than on 14 consecutive days. A transient 
increase in neutrophil counts is typically seen 1 to 
2 days after initiation of tbo-filgrastim therapy 
followed by the chemotherapy induced nadir.
Daily dosing with tbo-filgrastim should continue 
until the expected neutrophil nadir is passed and the 
neutrophil count has recovered to 2.0 × 109/L but 
not longer than on 14 consecutive days. A transient 
increase in neutrophil counts is typically seen 1 to 
2 days after initiation of tbo-filgrastim therapy 
followed by the chemotherapy induced nadir.
The minimum requirement of 5 daily doses of tbo-
filgrastim has been deleted in response to the 
FDA’s concern that requiring at least 5 daily doses 
is inconsistent with the dosage in the labeling and 
the current standard of care. Clarification of the 
transient increase in neutrophil counts typically 
seen 1 to 2 days after initiation of tbo-filgrastim 
therapy has been added.
3.11. Study Procedures
Table 1: Study Procedures and Assessments, Footnote a
a Daily dosing with tbo-filgrastim At least 5 daily 
doses of tbo filgrastim will be administered in this 
cycle and administration should continue until the 
expected neutrophil nadir is passed and the 
neutrophil count has recovered to 2.0 × 109/L, but 
not longer than on 14 consecutive days. A transient 
increase in neutrophil counts is typically seen 1 to 
2 days after initiation of tbo-filgrastim therapy 
followed by the chemotherapy induced nadir.
a Daily dosing with tbo-filgrastim should continue 
until the expected neutrophil nadir is passed and the 
neutrophil count has recovered to 2.0 × 109/L but 
not longer than on 14 consecutive days. A transient 
increase in neutrophil counts is typically seen 1 to 
2 days after initiation of tbo-filgrastim therapy 
followed by the chemotherapy induced nadir.
The minimum requirement of 5 daily doses of tbo-
filgrastim has been deleted in response to the 
FDA’s concern that requiring at least 5 daily doses
is inconsistent with the dosage in the labeling and 
the current standard of care. Clarification of the 
transient increase in neutrophil counts typically 
seen 1 to 2 days after initiation of tbo-filgrastim 
therapy has been added.


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17.2.
Amendment 01 Dated 11 January 2016
The primary reason for this amendment is to clarify the minimum number of 5 daily doses of 
tbo-filgrastim in the CTX cycle.
Table 1 (Study Procedures and Assessments) has been revised to reflect changes described 
below.
The revisions listed below have been made to the protocol (and protocol synopsis, as 
appropriate) and are considered substantial by the Teva Authorized Representative.
In addition, a page for the Coordinating Investigator Agreement was added, as 
 became 
known.


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Table 6:
Changes to the Protocol Amendment 01
Original text with changes shown
New wording
Reason/Justification for change
Title Page
This document contains confidential and proprietary information 
(including confidential commercial information pursuant to 
21CFR§20.61) and is a confidential communication of TEVA 
Branded Pharmaceutical Products R&D, Inc., and its affiliate, 
Cephalon Inc. (collectively the “Sponsor”). The recipient agrees 
that no information contained herein may be published or 
disclosed without written approval from the Sponsor.
This document contains confidential and proprietary information 
(including confidential commercial information pursuant to 
21CFR§20.61) and is a confidential communication of Teva 
Branded Pharmaceutical Products R&D, Inc., and its affiliate, 
Sicor Biotech UAB (collectively the “Sponsor”). The recipient 
agrees that no information contained herein may be published or 
disclosed without written approval from the Sponsor.
This document contains confidential and proprietary
information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a 
confidential communication of Teva Branded 
Pharmaceutical Products R&D, Inc., and its affiliate, 
Sicor Biotech UAB (collectively the “Sponsor”). The 
recipient agrees that no information contained herein 
may be published or disclosed without written approval 
from the Sponsor.
The confidentiality statement has 
been updated to reflect Sicor Biotech 
UAB as the applicant for the BLA.
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS
The following are to be decided:
Central Clinical Lab
To be provided in a separate laboratory guideline.
The identity of the clinical 
laboratory has been decided at the 
time of the amendment
Bioanalytical Lab
Global Bioassays and Technology, TEVA Pharmaceuticals USA
(ADA analysis)
Global Bioassays and Technology, TEVA 
Pharmaceuticals USA (ADA analysis)
The Teva laboratory is used for 
immunogenicity analysis.
 is used for 
pharmacokinetic sample analysis.
Central IRB
TBD
The identity of the Central IRB has 
been decided at the time of the 
amendment.


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Original text with changes shown
New wording
Reason/Justification for change
Central Electrocardiogram Evaluation
To be provided in a separate ECG guideline.
Central ECG Evaluation
The identity of the Central 
Electrocardiogram Evaluation has 
been identified.
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the physician listed below: 
For medical issues, contact the physician listed 
below: 
An additional physician was added
as a contact for medical issues. 
For operational issues, contact the operational lead listed 
below:
For operational issues, contact the operational lead 
listed below: 
The contact operational lead has 
changed.
Clinical Study Protocol Synopsis (Other sections affected by this change: List of Abbreviations, Section 1.1, Section 3.4.4.1, 
Name of Investigational Product: Tbo-filgrastim (the 
investigational product in this study, has been approved as a 
biosimilar to filgrastim [Neupogen] in the European Union, under 
the product names Tevagrastim, Ratiograstim and Biograstim 
[international nonproprietary name: filgrastim], and has the Teva 
product code XM02. It has been approved under the product name 
Granix [United States approved name {USAN}: tbo-filgrastim] in 
the United States of America (USA) via a Biologic License 
Application (BLA). To retain a consistent nomenclature 
throughout this protocol that distinguishes the investigational 
product from filgrastim [Neupogen], the investigational product is 
termed “tbo-filgrastim”.
Name of Investigational Product: Tbo-filgrastim (the 
investigational product in this study, has been approved 
as a biosimilar to filgrastim [Neupogen] in the European 
Union, under the product names Tevagrastim, 
Ratiograstim and Biograstim [international 
nonproprietary name: filgrastim], and has the Teva 
product code XM02. It has been approved under the 
product name Granix [tbo-filgrastim] in the United 
States of America (USA) via a Biologic License 
Application (BLA). To retain a consistent nomenclature 
throughout this protocol that distinguishes the 
investigational product from filgrastim [Neupogen], the 
investigational product is termed “tbo-filgrastim”.
Removal of references to the USAN, 
since an USAN name was not 
assigned.
Study Drug Dose, Mode of Administration, and Administration Rate:
Tbo filgrastim is a biosimilar of Neupogen filgrastim, a human G 
Tbo filgrastim, a human G CSF, is a biosimilar of 
Clarification that tbo-filgrastim is a 


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Original text with changes shown
New wording
Reason/Justification for change
CSF. a human G CSF, is a biosimilar of filgrastim (Neupogen) in 
the EU.
filgrastim (Neupogen) in the EU.
biosimilar to Neupogen in the EU.
Clinical Study Protocol Synopsis (Other section affected by this change: Section 3.10)
Number of Investigational Centers Planned: 15 Approximately 
30
Number of Investigational Centers Planned:
Approximately 30
The number of investigational 
centers was changed to 
approximately 30.
Countries Planned: Central and Eastern Europe, and the United 
States of America
Countries Planned: Central and Eastern Europe and the 
United States of America
The regions have been specified.
Planned Study Period: SeptemberMay 2014 2015 to 
JuneNovember 2016
Planned Study Period: May 2015 to November 2016
First Patient In was in May 2015. 
The study plan schedule was 
adjusted accordingly.
1.2 Name and Description of Investigational Product
Tbo-filgrastim (also known as XM02 and Neutroval) is a 
non-glycosylated r-metHuG-CSF expressed in Escherichia coli, 
and has a molecular weight of 18,798.98 Daltons. Tbo-filgrastim 
was developed as a biosimilar to filgrastim, the active substance in 
EU-sourced Neupogen.
Tbo-filgrastim (also known as XM02) is a 
non-glycosylated r-metHuG-CSF expressed in 
Escherichia coli, and has a molecular weight of 
18,798.98 Daltons. Tbo-filgrastim was developed as a 
biosimilar to filgrastim, the active substance in EU-
sourced Neupogen.
Neutroval was not an accepted trade 
name by the regulatory authorities.
3. STUDY DESIGN
3.1. General Design and Study Schema (Other sections affected by this change: Section 3.4.1.4, Section 5.1, and Clinical Study Protocol Synopsis)
At least 5 Ddaily doses of tbo-filgrastim may will be administered 
for up to 14 consecutive days in this cycle, and administration 
should continue but only until the expected neutrophil nadir is 
passed and the neutrophil count has recovered to 2.0 × 109/L., but 
not longer than on 14 consecutive days.
At least 5 daily doses of tbo-filgrastim will be 
administered in this cycle, and administration should 
continue until the expected neutrophil nadir is passed 
and the neutrophil count has recovered to 2.0 × 109/L, 
but not longer than on 14 consecutive days.
The minimum duration of daily 
dosing of tbo-filgrastim was clarified 
since it is not expected that the 
neutrophil nadir will be passed
before 5 days.
3.1. General Design and Study Schema (Other sections affected by this change: Section 3.5 and Clinical Study Protocol Synopsis)
The maximum duration of the study for an individual patient 
(from screening period until the end of the 90- day follow-up 
period) will be approximately 9 weeks (approximately 18 weeks 
for the 90 day anti drug antibody [ADA] sample).
The maximum duration of the study for an individual 
patient (from screening period until the end of the 90-
day follow-up period) will be approximately 18 weeks.
Editorial, sentence rewritten.
3.6.1 Early Discontinuation
Early termination procedures will be completed within 5 days (±2 
days) after the site has been informed of a patient’s decision to 
discontinue the study, or the investigator has decided to withdraw 
a patient.
Procedures will be completed within 5 days (±2 days) 
after the site has been informed of a patient’s decision to 
discontinue the study, or the investigator has decided to 
withdraw a patient.
Editorial
3.10. Time Schedule
Details in this section are to be decided.
Sentence is redundant.
The study is expected to started in September May 2014 2015 and The study started in May 2015 and is expected to be 
First Patient In was in May 2015. 


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Original text with changes shown
New wording
Reason/Justification for change
is expected to be completed in June November 2016, with a 
duration of about 3319 months.
completed in November 2016, with a duration of about 
19 months.
The study plan schedule was 
adjusted accordingly.
Approximately 50 (minimum 30) patients from 15 approximately 
30 investigational centers are planned to be enrolled in the study.
Approximately 50 (minimum 30) patients from 
approximately 30 investigational centers are planned to 
be enrolled in the study.
The number of investigational 
centers was changed to 
approximately 30.
The study is planned to be conducted in Central and Eastern 
Europe, including Russia and Ukraine, and the United States of 
America.
The study is planned to be conducted in Central and 
Eastern Europe, and the United States of America.
The regions have been specified.
3.11. Study Procedures
Table 1: Study Procedures and Assessments, heading in “Follow-up” column
30 (±3) and 90 (±6) days from last tbo-filgrastim administration in 
CTX Cycle 1
30 (±3) and 90 (±6) days from last tbo-filgrastim 
administration in CTX Cycle 1
Time windows were specified.
Table 1: Study Procedures and Assessments, Footnote a (Other section affected by this change: Section 5.1) 
a Tbo filgrastim may be administered for up to 14 consecutive 
days, but only until the expected neutrophil nadir is passed and the 
neutrophil count has recovered to at least 2.0 × 109/L. At least 
5 daily doses of tbo-filgrastim will be administered in this cycle, 
and administration should continue until the expected neutrophil 
count has recovered to 2.0 × 109/L, but not longer than on 
14 consecutive days.
aAt least 5 daily doses of tbo-filgrastim will be 
administered in this cycle, and administration should 
continue until the expected neutrophil nadir is passed 
and the neutrophil count has recovered to 2.0 × 109/L, 
but not longer than on 14 consecutive days.
The minimum duration of daily 
dosing of tbo-filgrastim was clarified 
since it is not expected that the 
neutrophil nadir will be passed
before 5 days.
Footnote “a” was cross referenced to 
clarify the duration of tbo-filgrastim 
administration during the time period 
of Days 2-15.
Table 1: Study Procedures and Assessments, Footnote c (Other section affected by this change: Section 6.7.1)
c Concomitant therapy or medication will be recorded after the 
ICF is signed, and throughout the study treatment period, and until 
30 days from last tbo-filgrastim administration.
c Concomitant therapy or medication will be recorded 
after the ICF is signed, and throughout the study 
treatment period, and until 30 days from last tbo-
filgrastim administration.
A footnote was added to clarify the 
recording time of concomitant 
medications.
Table 1: Study Procedures and Assessments, Footnote f
f Repeat ECGs at pre-dose, 4 and 6 hours after first tbo-filgrastim 
in addition to screening and end of study assessment. A window 
of ±15 minutes is allowed.
f Repeat ECGs at pre-dose, 4 and 6 hours after first 
tbo-filgrastim in addition to screening and end of study 
assessment. A window of ±15 minutes is allowed.
A window for repeat ECGs was 
specified within the existing 
footnote. 
Table 1: Study Procedures and Assessments, Footnote h )
h Adverse events will be recorded after the ICF is signed, and 
throughout the study treatment period, and until 30 days from last 
tbo-filgrastim administration..
h Adverse events will be recorded after the ICF is signed, 
and throughout the study treatment period, and until 
30 days from last tbo-filgrastim administration.
A footnote was added to clarify the 
recording time for adverse events.
Table 1: Study Procedures and Assessments, Footnote j
j On day 1, ie, 24 hours (±3 hours) after the end of last CTX in 
week 1. Administration of tbo-filgrastim is from day 1 but not 
j On day 1, ie, 24 hours (±3 hours) after the end of last 
CTX in week 1. Administration of tbo-filgrastim is from 
The administration period of tbo-
filgrastim was indicated within the 


Pediatric Study–Chemotherapy-Induced Neutropenia
Clinical Study Protocol with Amendment 02
Study XM02-ONC-201
89
Original text with changes shown
New wording
Reason/Justification for change
longer than up to day 14.
day 1 but not longer than up to day 14.
footnote for clarification 
3.11.1. Procedures for Screening and Enrollment (Other section affected by this change: Section 6.3)
In case the results from the central laboratory will not be available 
on day 1 before start of CTX, the investigator may use test results 
from local laboratories in order to initiate CTX.
In case the results from the central laboratory will not be 
available on day 1 before start of CTX, the investigator 
may use test results from local laboratories in order to 
initiate CTX.
Permission to use local lab results 
for inclusion in exceptional cases to 
facilitate timely beginning of 
chemotherapy for treatment of the 
children.
3.11.3.2. Day 2 to Day 15

administer tbo-filgrastim not longer than up to day14.

administer tbo-filgrastim not longer than up to
day 14.
Text was amended for clarification 
of duration for tbo-filgrastim 
administration.
3.11.5.
Procedures After Study Drug Treatment
The following procedures/assessments will be performed at 
30 (±3) and 90 (±6) days after the last tbo-filgrastim 
administration in CTX cycle 1:
The following procedures/assessments will be 
performed at 30 (±3) and 90 (±6) days after the last 
tbo-filgrastim administration in CTX cycle 1:
Time windows were specified.
record adverse events (only until 30 days after the last 
tbo-filgrastim administration).
record adverse events (only until 30 days after the last 
tbo-filgrastim administration).
The time period for recording 
adverse events was indicated.
record concomitant medication (only until 30-days after the last 
tbo filgrastim administration).
record concomitant medication (only until 30 days after 
the last tbo filgrastim administration).
The time period for recording 
concomitant medications was 
indicated. 
4.
SELECTION AND WITHDRAWAL OF PATIENTS
4.2. Patient Exclusion Criteria (Other sections affected by this change: Clinical Study Protocol Synopsis)
l.
[New criterion] Participation in an interventional clinical 
study within 30 days or 5-half-lives of the investigational product 
before enrollment, whichever is longer.
l. [New criterion] Participation in an interventional 
clinical study within 30-days or 5-half-lives of the 
investigational product before enrollment, whichever is 
longer.
A new exclusion criterion was added 
as a Teva standard.
6.
ASSESSMENT OF SAFETY
Section 6.1.1 Definition of an Adverse Event
In this study, any adverse event occurring after the clinical study 
patient has signed the informed consent form ICF has been signed
and throughout the study treatment period, and until 30-days from 
last tbo-filgrastim administration, should be recorded and reported 
as an adverse event.
In this study, any adverse event occurring after the ICF 
has been signed and throughout the study treatment 
period, and until 30-days from last tbo-filgrastim 
administration, should be recorded and reported as an 
adverse event. 
The time frame for recording an 
adverse event was indicated. 
Section 6.1.2 Recording and Reporting Adverse Events
Adverse events will be recorded from the time a patient’s 
parent(s) or legal representative(s) has signed the informed 
consent form ICF (and the adolescent patient has given informed 
assent) and throughout the study treatment period ending with the 
Adverse events will be recorded from the time a 
patient’s parent(s) or legal representative(s) has signed 
the ICF (and the adolescent patient has given informed 
assent) and throughout the study treatment period and 
The time frame for recording an 
adverse event was indicated.


Pediatric Study–Chemotherapy-Induced Neutropenia
Clinical Study Protocol with Amendment 02
Study XM02-ONC-201
90
Original text with changes shown
New wording
Reason/Justification for change
end of study and until 30-days from the last tbo-filgrastim 
administration assessment. They should be reviewed and updated 
at each subsequent visit within this period.
until 30-days from the last tbo-filgrastim administration. 
They should be reviewed and updated at each 
subsequent visit within this period.
Section 6.1.5.2. Expectedness
The reference safety information for this study is the 
Investigator’s Brochure. US prescribing information.
The reference safety information for this study is the 
Investigator’s Brochure.
The Investigator’s Brochure is now 
the reference safety information.
Section 7.1.2 Blood Sampling and Handling
Storage at -20°C is acceptable provided that the samples are 
shipped within 3 to 5 days from collection.
Storage at -20°C is acceptable provided that the samples 
are shipped within 3 to 5 days from collection.
Storage conditions for blood samples 
have been specified.

SAP_001.pdf: 
Statistical Analysis Plan
A Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics,
Pharmacodynamics, Efficacy, and Immunogenicity of Daily Subcutaneous Administration 
of 5 μg/kg tbo-filgrastim in Infants, Children and Adolescents with Solid Tumors without 
Bone Marrow Involvement
Study XM02-ONC-201
NCT02190721
Date: 26 January 2017


Statistical Analysis Plan
Study XM02-ONC-201
1
 
STATISTICAL ANALYSIS PLAN
TEVA Pharmaceutical Industries Ltd
Study XM02-ONC-201
A Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, Efficacy, and Immunogenicity of Daily Subcutaneous Administration 
of 5 µg/kg tbo-filgrastim in Infants, Children and Adolescents with Solid Tumors without 
Bone Marrow Involvement
Phase 2
Date: 26-JAN-2017
Version: Final V2.0
Prepared by:
TEVA Statistician:


Statistical Analysis Plan
Study XM02-ONC-201
2
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................6
List of Abbreviations .......................................................................................................................6
List of Key Study Terms..................................................................................................................7
PREFACE . .....................................................................................................................................8
1.
STUDY OBJECTIVES ................................................................................................9
1.1.
Primary Objectives .......................................................................................................9
1.2.
Secondary Objectives ...................................................................................................9
2.
STUDY DESIGN .......................................................................................................10
2.1.
General Design and Study Schema.............................................................................10
2.2.
Primary and Secondary Measures and Endpoints ......................................................14
2.2.1.
Primary Measures and Endpoints...............................................................................14
2.2.2.
Immunogenicity Measures and Endpoints..................................................................14
2.2.3.
Pharmacokinetic Measures and Endpoints.................................................................14
2.2.4.
Pharmacodynamic Measures and Endpoints ..............................................................15
2.2.5.
Efficacy Measures and Endpoint................................................................................15
2.3.
Study Drugs ................................................................................................................15
2.4.
Randomization and Blinding......................................................................................15
2.5.
Sample Size and Power Considerations .....................................................................16
3.
ASSESSMENTS AND ENDPOINTS........................................................................17
3.1.
Patient Characteristics ................................................................................................17
3.1.1.
Demographic Data and Baseline Characteristics........................................................17
3.1.2.
Medical History ..........................................................................................................17
3.2.
Drug Exposure............................................................................................................17
3.2.1.
Study Drug Administration.........................................................................................17
3.2.2.
Prior and Concomitant Medication.............................................................................17
3.3.
Pharmacokinetic Measures and Endpoints.................................................................18
3.4.
Pharmacodynamic Measures and Endpoints ..............................................................18
3.5.
Efficacy Assessments .................................................................................................18
3.6.
Safety Assessments.....................................................................................................18
3.6.1.
Adverse Events ...........................................................................................................18


Statistical Analysis Plan
Study XM02-ONC-201
3
3.6.2.
Clinical Laboratory Tests ...........................................................................................19
3.6.3.
Vital Signs ..................................................................................................................19
3.6.4.
Electrocardiography (ECG)........................................................................................19
3.6.5.
Physical Examination .................................................................................................19
3.6.6.
Local Tolerability at the Injection Site.......................................................................20
3.6.7.
Spleen Sonography.....................................................................................................20
3.6.8.
Immunogenicity Assessment......................................................................................20
3.7.
Follow-Up Assessments .............................................................................................20
3.7.1.
Survival Status............................................................................................................20
3.7.2.
Immunogenicity Assessment......................................................................................20
3.7.3.
Concomitant Medication ............................................................................................20
4.
ANALYSIS POPULATIONS ....................................................................................21
4.1.
Intent-to-Treat Population ..........................................................................................21
4.2.
Safety Analysis Set.....................................................................................................21
4.3.
Full Analysis Set.........................................................................................................21
4.4.
Pharmacokinetic Analysis Set ....................................................................................21
5.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................22
5.1.
General Considerations...............................................................................................22
5.2.
Specification of Baseline Values................................................................................22
5.3.
Stratification Criteria/Sub-group Analysis Sets..........................................................22
5.4.
Multiple Comparisons and Multiplicity......................................................................22
5.5.
Handling of Withdrawals and Missing Data ..............................................................22
5.6.
Study Days and Visit Windows..................................................................................23
5.7.
Sequence of Planned Analyses ...................................................................................23
5.7.1.
Interim Analyses.........................................................................................................23
5.7.2.
Final Analyses and Reporting.....................................................................................24
6.
STATISTICAL ANALYSIS ......................................................................................25
6.1.
Study Population.........................................................................................................25
6.1.1.
General........................................................................................................................25
6.1.2.
Patient Disposition......................................................................................................25
6.1.3.
Demographics and Baseline Characteristics...............................................................25
6.1.4.
Actual Chemotherapy.................................................................................................25
6.1.5.
Medical History ..........................................................................................................25


Statistical Analysis Plan
Study XM02-ONC-201
4
6.1.6.
Prior Medications........................................................................................................26
6.1.7.
Electrocardiography....................................................................................................26
6.1.8.
Physical Examinations................................................................................................26
6.1.9.
Protocol Violations.....................................................................................................26
6.1.10.
Childbearing Potential ................................................................................................26
6.2.
Safety Analysis ...........................................................................................................26
6.2.1.
General........................................................................................................................26
6.2.2.
Study Drug Administration.........................................................................................26
6.2.3.
Adverse Events ...........................................................................................................27
6.2.4.
Deaths .........................................................................................................................28
6.2.5.
Clinical Laboratory Tests ...........................................................................................28
6.2.6.
Vital Signs ..................................................................................................................29
6.2.7.
Electrocardiography....................................................................................................29
6.2.8.
Physical Examinations................................................................................................30
6.2.9.
Local Tolerability Assessments..................................................................................30
6.2.10.
Spleen Sonography.....................................................................................................30
6.2.11.
Immunogenicity..........................................................................................................30
6.2.12.
Concomitant Medication ............................................................................................30
6.3.
Pharmacokinetic Analysis ..........................................................................................31
6.3.1.
General........................................................................................................................31
6.3.2.
Summary of Drug Concentration Data.......................................................................31
6.3.3.
Calculation of Pharmacokinetic Parameters...............................................................31
6.3.4.
Statistical Analyses of Pharmacokinetic Parameters..................................................33
6.4.
Pharmacodynamics Analysis......................................................................................33
6.4.1.
Calculation of Pharmacodynamics Parameters ..........................................................33
6.4.2.
Statistical Analyses of Pharmacodynamics ................................................................34
6.5.
Efficacy Analysis........................................................................................................35
6.5.1.
General........................................................................................................................35
6.5.2.
Key Efficacy Variable and Analysis...........................................................................35
6.5.3.
Additional Efficacy Variable and Analysis ................................................................35
6.6.
Follow-Up Data ..........................................................................................................36
6.6.1.
Survival Status............................................................................................................36
6.6.2.
Immunogenicity Assessments ....................................................................................36


Statistical Analysis Plan
Study XM02-ONC-201
5
6.6.3.
Concomitant Medication during Follow-Up ..............................................................36
7.
CHANGES TO PROTOCOL SPECIFIED ANALYSES ..........................................37
8.
REFERENCES ...........................................................................................................38
9.
STATISTICAL ANALYSIS PLAN APPROVAL.....................................................39
LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................11
Table 2:
Pharmacokinetic and Pharmacodynamic Assessments ..............................................13
Table 3:
Criteria for Potentially Clinically Significant Vital Signs..........................................29
Table 4:
Derivation of Pharmacokinetic Parameters ................................................................31
Table 5:
Derivation Method for Pharmacodynamics Parameters.............................................33


Statistical Analysis Plan
Study XM02-ONC-201
6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
List of Abbreviations
ADA
anti-drug antibody
ANC
absolute neutrophil count
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUCANC
area under the curve of absolute neutrophil count
AUC0-12
area under the serum concentration-time curve from time 0 to 12 hours postdose
AUC0-inf
area under the serum concentration-time curve from time 0 to infinity
AUClast
area under the serum concentration-time curve from time 0 to time of last quantifiable 
concentration
BQL
below quantifiable limit
CI
confidence interval
Cmax
maximum observed serum concentration
CL/F
apparent clearance
CRF
case report form
CSR
clinical study report
CTX
chemotherapy
CV
coefficient of variation
DMC
Data Monitoring Committee
DSN
duration of severe neutropenia
ECG
electrocardiography, electrocardiogram
FAS
full analysis set
FN
febrile neutropenia
GM
geometric mean
ICH
International Council for Harmonisation
ITT
intent-to-treat
z
terminal elimination rate
LOCF
last observation carried forward
LSMeans
least squares means
MedDRA
Medical Dictionary for Regulatory Activities


Statistical Analysis Plan
Study XM02-ONC-201
7
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PD
pharmacodynamics
PK
pharmacokinetics
QTcB
QT interval according to Bazett’s formula
QTcF
QT interval according to Fridericia’s formula
SAF
safety analysis set
SAP
Statistical Analysis Plan
SD
standard deviation
tmax
time to maximum observed concentration
t½
elimination half-life
TEAE
treatment emergent adverse event
Vz/F
apparent volume of distribution during terminal phase
WHO Drug
World Health Organization drug dictionary
List of Key Study Terms
Term
Definitions
Febrile neutropenia
ANC <0.5 × 109/L and an axillary or external ear temperature 
>38.3°C or 2 consecutive readings >37.8°C for 2 hours (ie, 2 
consecutive readings at least 2 hours apart)
Severe neutropenia
ANC<0.5 × 109/L


Statistical Analysis Plan
Study XM02-ONC-201
8
PREFACE
The purpose of this Statistical Analysis Plan (SAP) is to provide details on the statistical methods
planned for the analyses and presentation of the data from Study XM02-ONC-201 as 
summarized in the study protocol (see below). Further specifications on tables, listings and 
figures to be produced will be provided as a separate document (XM02-ONC-201 Tables, 
Listings, and Figures Shells).
Further details on the study objectives, design, study drug administration, assessments, and 
procedures are described in Study Protocol XM02-ONC-201, dated 24 February 2016. 
This SAP will be finalized before database lock for the treatment period data. Data from the 
main part of the study (from screening to the end of the treatment period) will be analysed and 
reported upon completion of that study part. Data collected during the follow-up period of the 
study will be reported separately upon completion of the follow-up period (see Section 5.7.2 ).
Immunogenicity data will be presented in a separate report.
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA) and International Council for 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 
(ICH): E9 Guidance on Statistical Principles in Clinical Trials. All work planned and reported 
for this SAP will follow internationally accepted guidelines.
The following documents were reviewed in preparation of this SAP:

Clinical Study Protocol XM02-ONC-201 issued 24 February 2016.

Case report forms (CRFs) for Study XM02-ONC-201.

ICH E9 Guidance on Statistical Principles for Clinical Trials.

ICH E3 Structure and Content of Clinical Study Reports.
The reader of this SAP is encouraged to also read the clinical study protocol for details on the 
conduct of this study, and the operational aspects of clinical assessments and timing for 
completing a patient in this study. When differences exist in descriptions or explanations 
provided in the protocol and this SAP, the SAP prevails; the discrepancies will be explained in 
the clinical study report (CSR). 
All changes from the analysis specified in this SAP will be documented in the CSR.


Statistical Analysis Plan
Study XM02-ONC-201
9
1.
STUDY OBJECTIVES
1.1.
Primary Objectives
The primary objective of the study is to assess the safety and tolerability of 5 µg/kg 
tbo-filgrastim in the pediatric population with solid tumors without bone marrow involvement.
1.2.
Secondary Objectives
The secondary objectives are to assess the pharmacokinetics using sparse sampling strategy, 
pharmacodynamics, efficacy, and immunogenicity of tbo-filgrastim in this patient population.


Statistical Analysis Plan
Study XM02-ONC-201
10
2.
STUDY DESIGN
2.1.
General Design and Study Schema
This is a Phase 2, multicenter, open-label study to evaluate the safety, tolerability, 
pharmacokinetics, pharmacodynamics, efficacy, and immunogenicity of tbo-filgrastim at a dose 
of 5 µg/kg/day in infants, children, and adolescents with solid tumors without bone marrow 
involvement scheduled to receive at least 1 cycle of chemotherapy (CTX).
Three groups stratified by age (1 month to <2 years, 2 to <12 years, and 12 to <16 years) will be 
enrolled. Recruitment of patients in the youngest age stratum (1 month to <2 years) will begin 
only once safety (from the start of study to CTX-day 21) and pharmacodynamic (from the start 
of study to day 15 [relative to first tbo-filgrastim administration]) results are available for a 
minimum of 6 patients in the middle age stratum and have been reviewed by the Data 
Monitoring Committee (DMC) and no significant safety signals that prevent recruitment in the 
youngest age stratum have been detected.
Tbo-filgrastim administration will be started approximately 24 hours (±3 hours) after the end of 
the last CTX treatment in the first week of this CTX cycle. Daily dosing with tbo-filgrastim 
should continue until the expected neutrophil nadir is passed and the neutrophil count has 
recovered to 2.0 × 109/L but no longer than on 14 consecutive days.
The study will consist of 3 periods: screening period, treatment period, and follow-up period.
Screening period: Screening to confirm eligibility must be completed in 14 days or less prior to 
the initiation of CTX.
Treatment period: Patients will be treated for at least 1 cycle of CTX. The treatment period 
begins at the start of the first cycle of CTX administered under this protocol and ends at the end 
of this cycle (possibly immediately followed by further out-of-study CTX cycles). This period 
may last up to 3 weeks. The first dose of tbo-filgrastim will be administered 24 hours (±3 hours) 
after the end of last CTX in week 1 of this CTX cycle.
Follow-up period: The follow-up period includes survival assessment, recording of concomitant 
medications, and collection of an immunogenicity sample at 30 days and 3 months after last 
tbo-filgrastim study drug administration in the first cycle.
During the conduct of the study, an independent DMC will review accumulating and aggregated 
safety data on a regular basis to ensure the continuing safety of the study patients and study 
conduct issues.
Patients who complete all scheduled visits will have final procedures and assessments performed 
at the end-of-study visit. Patients who withdraw from the study before completing the evaluation 
period will have end-of-study procedures and assessments performed at their final visit.
Visit-specific procedures and assessments are outlined in Table 1 and Table 2.


Statistical Analysis Plan
Study XM02-ONC-201
11
Table 1:
Study Procedures and Assessments
Screening
Treatment Period
Follow-up
CTX Cycle 1
CTX in Week 1
tbo-filgrastim administrationa
End of Study Visit
Procedure
Days
CTX-D-14 
to CTX-D1
CTX-D1b
CTX-D2 to 
last CTX in 
Week 1
D1
(at 24 (± 3) hours 
after end of last 
CTX in Week 1)
D2 to D15 CTX-Day 21 (± 2) days; 
after PD period (and 
prior to next CTX cycle)
30 (± 3) and 90 (± 6) days 
from last tbo-filgrastim
administration in CTX Cycle 1
Informed consent
X
Medical and psychiatric history
X
Medication history
X
Concomitant medicationc
X
X
X
X
X
X
Urine drug screen
X
Height and weight
X
Evaluation of eligibility 
X
Urine pregnancy testd
X
X
Physical examination
X
X
Vital signse
X
X
X
X
X
X
12-Lead ECGf
X
X
X
Serum chemistry
X
X
Hematology
X
X
Spleen sonographyg
X
X
X
Adverse event evaluationh
X
X
X
X
X
X
Xh
Chemotherapy administration
X
Xi
Xi
tbo-filgrastim administration
Xj
Xa
Local tolerability at injection site
Xk
Xk


Statistical Analysis Plan
Study XM02-ONC-201
12
Screening
Treatment Period
Follow-up
CTX Cycle 1
CTX in Week 1
tbo-filgrastim administrationa
End of Study Visit
Procedure
Days
CTX-D-14 
to CTX-D1
CTX-D1b
CTX-D2 to 
last CTX in 
Week 1
D1
(at 24 (± 3) hours 
after end of last 
CTX in Week 1)
D2 to D15 CTX-Day 21 (± 2) days; 
after PD period (and 
prior to next CTX cycle)
30 (± 3) and 90 (± 6) days 
from last tbo-filgrastim
administration in CTX Cycle 1
PK assessment
Xl
PD assessment (ANC) 
Xl
Xl
ADA assessment
X
X
X
Survival
X
a Daily dosing with tbo-filgrastim should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to 2.0 x 109/L but not 
longer than on 14 consecutive days. A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of tbo-filgrastim therapy followed by 
the chemotherapy induced nadir.
b All screening procedures can be performed on day 1 prior to start of CTX, as long as all laboratory/diagnostic results are available prior to start of CTX.
c Concomitant therapy or medication will be recorded after the ICF is signed, and throughout the study treatment period, and until 30-days from last tbo-
filgrastim administration.
d For female patients of child-bearing potential.
e Vital signs (blood pressure, pulse rate, respiration rate, and body temperature) should be obtained at each visit. Body temperature (axillary or external ear) is to 
be obtained twice daily (morning and evening) and recorded in the patient diary and CRF.
f Repeat ECGs at pre-dose, 4 and 6 hours after first tbo-filgrastim in addition to screening and end of study assessment. A window of ±15 minutes is allowed.
g Spleen sonography to be conducted at screening, on day 4 of tbo-filgrastim treatment, at the end of study assessment, and if the patient reports left upper 
abdominal and/or shoulder tip pain.
h Adverse events will be recorded after the ICF is signed, throughout the study treatment period, and until 30 days from last tbo-filgrastim administration.
i Additional CTX treatments as per patient’s specific regimen.
j On day 1, ie, 24 hours (±3 hours) after the end of last chemotherapy in week 1. Administration of tbo-filgrastim is from day 1 but not longer than up to day 14.
k Tolerability assessment at 1 hour (±30 minutes) after the tbo-filgrastim administration.
l See Table 2 for a detailed schedule of PK and PD assessments.
CTX-Dx = days of chemotherapy cycle 1; Dx = study days of tbo-filgrastim treatment period; ECG = electrocardiography; PD=pharmacodynamic.


Statistical Analysis Plan
Study XM02-ONC-201
13
Table 2:
Pharmacokinetic and Pharmacodynamic Assessments
Procedure
Prior to tbo-
filgrastim dose 
on D1a
PK Assessments on day 1
Hours after first tbo-filgrastim dose 
PD Assessment
Day after first tbo-filgrastim dose
2
4
6
8
12
D5
D6
D7
D10
D12
D15
PK blood sample
X
X
X
X
X
X
PD blood sample for ANC
X
X
X
X
X
X
Xb
a Samples are to be obtained within 1 hour prior to the tbo-filgrastim dose.
b Optional if day 15 coincides with CTX-day 21 (ANC will be part of scheduled hematology sample on CTX-day 21).
ANC=absolute neutrophil count; PK=pharmacokinetic; PD=pharmacodynamic


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Study XM02-ONC-201
14
2.2.
Primary and Secondary Measures and Endpoints
2.2.1.
Primary Measures and Endpoints
The primary endpoint is the safety of tbo-filgrastim. This includes adverse event during the 
study, local tolerability, spleen sonography assessments, and if the patient reports left upper 
abdominal and/or shoulder tip pain, and survival at 90-day follow-up.
The primary endpoint will be assessed by evaluating the following:

adverse event reports throughout the study

clinical laboratory test results at screening and at the end-of-study visit

vital signs measurements (blood pressure, pulse rate, respiration rate, and body 
temperature) at screening, throughout the study treatment, and at the end-of-study 
visit

electrocardiography (ECG) findings at screening, pre-dose, and 4 and 6 hours after 
the first tbo-filgrastim administration, and at the end-of-study visit

physical examination results at screening and at the end-of-study visit

concomitant medication usage throughout the study

local tolerability at the injection site at 1 hour (±30 min) after each study drug
injection

spleen sonography assessments at screening, on day 4 of tbo-filgrastim treatment, at 
the end-of-study visit, and if the patient reports left upper abdominal and/or shoulder 
tip pain

survival at 90-day follow-up.
2.2.2.
Immunogenicity Measures and Endpoints
The immunogenicity endpoints are:

ADA assessment prior to the first tbo-filgrastim administration, at the end-of-study 
visit, and at 30 days and 3 months after the last tbo-filgrastim study drug treatment in 
the first cycle.
2.2.3.
Pharmacokinetic Measures and Endpoints
The pharmacokinetic measure for this study is serum concentration of tbo-filgrastim.
The pharmacokinetic variables are as follows:

Maximum observed serum concentration (Cmax)

Time to Cmax (tmax)

Area under the serum concentration-time curve from time 0 to 12 hours postdose 
(AUC0-12)

AUC from time 0 to infinity (AUC0-inf)


Statistical Analysis Plan
Study XM02-ONC-201
15

AUC from time 0 to time of last quantifiable concentration (AUClast)

Elimination half-life (t1/2)

Terminal elimination rate (z)

Apparent clearance (CL/F)

Apparent volume of distribution during the terminal phase (Vz/F)

% AUCinf extrapolated
2.2.4.
Pharmacodynamic Measures and Endpoints
The pharmacodynamic measure for this study is absolute neutrophil count (ANC) in blood.
The pharmacodynamic variables are as follows:

incidence and duration of severe neutropenia (DSN), ANC <0.5 × 109/L

AUC of ANC (AUCANC)

ANC nadir (measured in 109/L), which is the lowest ANC recorded

time to ANC nadir from the beginning of tbo-filgrastim administration up to the 
occurrence of the ANC nadir

time to ANC nadir from the beginning of CTX up to the occurrence of the ANC nadir

time to ANC recovery to ≥1.0 × 109/L, and time to ANC recovery to ≥2.0 × 109/L 
from ANC nadir

time to ANC recovery to ≥1.0 × 109/L, and time to ANC recovery to ≥2.0 × 109/L 
from the beginning of tbo-filgrastim administration and from CTX-day 1
2.2.5.
Efficacy Measures and Endpoint
The efficacy measures for the study are axillary or external ear temperature and ANC in blood.
The efficacy variable is the incidence of febrile neutropenia (FN). This is defined in Section 3.5 .
2.3.
Study Drugs
Patients will receive subcutaneous doses of tbo-filgrastim 5 µg/kg body weight daily; each daily 
dose will be taken from a vial containing 300 µg/mL tbo-filgrastim.
The first dose of tbo-filgrastim should be administered not earlier than 24 hours (±3 hours) 
following the end of myelosuppressive CTX in week 1 of the cycle. Daily dosing with 
tbo-filgrastim should continue until the expected neutrophil nadir is passed and the neutrophil 
count has recovered to 2.0 x 109/L but not longer than on 14 consecutive days. A transient 
increase in neutrophil counts is typically seen 1 to 2 days after initiation of tbo-filgrastim therapy 
followed by the chemotherapy induced nadir.
2.4.
Randomization and Blinding
This is a nonrandomized, open-label study.


Statistical Analysis Plan
Study XM02-ONC-201
16
2.5.
Sample Size and Power Considerations
It is planned to enrol approximately 50 patients, in 15 to 30 investigational centers.
The overall sample size of 50 (at least 6 in the infants group, 1 month to <2 years; 12 in the 
children group, 2 to <12 years; and 12 in the adolescents group, 12 to <16 years) is not the result 
of a formal sample size calculation but was chosen for pragmatic reasons, taking into account the 
difficulty of recruiting patients in the requested age classes for such a study, and is considered 
sufficient to allow exploratory analysis. Data will be evaluated using statistical approaches for 
exploratory data analyses.


Statistical Analysis Plan
Study XM02-ONC-201
17
3.
ASSESSMENTS AND ENDPOINTS
3.1.
Patient Characteristics
3.1.1.
Demographic Data and Baseline Characteristics
The patient’s date of birth, (or alternatively the age), ethnicity, race and sex will be collected at 
the screening visit. Details of whether the patient is of childbearing potential and details of 
contraception use will also be recorded.
Age will also be collected in years for patients who are 5 years old or older, and in years and 
months for patients who are less than 5 years old if a complete date of birth is not given due to 
privacy laws. If a complete date of birth is given, then the age will be derived in whole years or 
years and months from the date of birth and date of informed consent. If a complete date of birth 
is not given due to privacy laws, then the age recorded will be used.
In addition, height and weight and the Lansky Performance Status score will be measured at the 
screening visit. The Lansky Performance Status score will only be collected for patients who are 
at least 1 year old.
3.1.2.
Medical History
Previous and ongoing general medical history will be recorded at the screening visit.
In addition, details of cancer history including tumor, lymph node, metastasis (TNM) status, 
tumor type, and stage and date of diagnosis will be collected. The type and date of any 
surgery/transplantation will also be recorded.
Time since diagnosis will be calculated in months as:
(Date of informed consent – date of diagnosis)/30.5
3.2.
Drug Exposure
3.2.1.
Study Drug Administration
The date and time of tbo-filgrastim administration, the planned dose, the actual dose and whether 
the total dose was administered will be recorded for each administration. Using this information 
for each patient, the number of tbo-filgrastim administrations and the total amount of 
tbo-filgrastim administered during the study will be derived.
3.2.2.
Prior and Concomitant Medication
Prior anticancer therapy (CTX and radiotherapy) will be recorded at the screening visit. Any 
concomitant therapy, medication, or procedure received from the screening to the end of the 
follow-up visits will be recorded.
In addition, details of CTX administration including the treatment (the combination of one or 
more of etoposide, cyclophosphamide, doxorubicin, or ifosfamide plus any other CTX therapy
received in addition), start and end date and time, planned dose, and actual dose will be recorded 
for each administration.


Statistical Analysis Plan
Study XM02-ONC-201
18
3.3.
Pharmacokinetic Measures and Endpoints
Blood samples (0.6 mL) will be collected within 1 hour before the tbo-filgrastim dose and at 2, 4, 
6, 8, and 12 hours after the tbo-filgrastim dose on day 1, for serum concentration measurements 
of tbo-filgrastim.
The pharmacokinetic variables to be calculated are listed in Section 2.2.3.
3.4.
Pharmacodynamic Measures and Endpoints
Blood samples (0.5 mL) for the assessment of ANC will be collected within 1 hour before the 
tbo-filgrastim dose on day 1, and on days 5, 6, 7, 10, 12, and 15. The sample on day 15 is 
optional if day 15 coincides with CTX-day 21.
The pharmacodynamic variables to be calculated are listed in Section 2.2.4.
3.5.
Efficacy Assessments
The efficacy variable is the incidence of FN. This is defined as an axillary or external ear 
temperature >38.3°C or 2 consecutive readings >37.8°C for 2 hours (ie, 2 consecutive readings at
least 2 hours apart) and ANC<0.5 × 109/L.
Whether or not the patient experienced FN and the date that this was observed will be captured 
in the CRF. In addition, details of which of the two temperature criteria are fulfilled, details of 
any hospitalization due to FN, and administration of systemic antibiotics and antipyretics will be 
recorded.
3.6.
Safety Assessments
3.6.1.
Adverse Events
Adverse events will be recorded from the time a patient’s parent(s) or legal representative(s) has 
signed the informed consent form (and the adolescent patient has given informed assent) and 
throughout the study treatment period ending with the end-of-studyvisit.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding the study drug, treatment administered, and outcome for each adverse event will 
be recorded in the CRF.
The severity of each adverse event will be graded from 1 to 5 according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events, current version 4.03 (NCI CTCAE 
version 4.03).
The relation to study drug and CTX will be characterized as ‘no reasonable possibility’ (not 
related), or ‘reasonable possibility’ (related).
Whether the adverse event was considered serious will also be recorded. Further details of 
reporting of serious adverse events are given in the study protocol Section 6.1.5.


Statistical Analysis Plan
Study XM02-ONC-201
19
3.6.2.
Clinical Laboratory Tests
Clinical laboratory tests (serum chemistry and hematology) will be performed at screening and at 
the end-of-study visit. Clinical laboratory tests will be performed using a central laboratory. The 
following specific laboratory tests are to be performed:
Serum chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, gamma-glutamyl 
transpeptidase, lactic dehydrogenase, glucose (non-fasting), uric acid, creatinine, calcium, 
sodium, potassium, and phosphate.
Hematology: hemoglobin, hematocrit, red blood cell count, platelet count, absolute and relative 
white blood cell count (WBC), neutrophils, lymphocytes, eosinophils, monocytes, and basophils.
In addition, urine pregnancy tests will be performed for all female patients of childbearing 
potential at screening and if clinically indicated thereafter. A urine drug screen will also be 
performed at screening.
3.6.3.
Vital Signs
Vital signs will be measured at all visits in accordance with the schedule of study procedures and 
assessments shown in Table 1. The vital signs measurementsd are pulse , systolic blood pressure, 
diastolic blood pressure, respiration rate, and body temperature (axillary or external ear). Body 
temperature will be measured twice daily during the study, once in the morning and once in the 
evening. Additional measurements will be taken if the patient feels feverish and if FN has to be 
confirmed.
3.6.4.
Electrocardiography (ECG)
Triplicate 12-lead ECGs will be conducted at screening, predose, 4 and 6 hours postdose on day 
1 of tbo-filgrastim administration, and at the end-of-study visit. The ECGs will be interpreted by 
both the investigator and a qualified physician at the central diagnostic center as normal, 
abnormal not clinically significant, or abnormal clinically significant.
The following parameters will be measured/derived for each ECG assessment: heart rate, PR 
interval, RR interval, QT interval, corrected QT interval according to Fridericia’s formula 
(QTcF), corrected QT interval according to Bazett’s formula (QTcB), QRS duration, and QRS 
axis.
3.6.5.
Physical Examination
Physical examination will be performed at screening and at the end-of-study visit. The following 
body systems will be marked as normal or abnormal and if abnormal, whether clinically 
significant:
Head, ears, eyes, nose and throat, chest and lungs, heart, abdomen, skin, lymph nodes and 
neurological.
Any physical examination finding that is judged by the investigator as a clinically significant 
change (worsening) compared with a baseline value will be considered as an adverse event. 


Statistical Analysis Plan
Study XM02-ONC-201
20
3.6.6.
Local Tolerability at the Injection Site
Local tolerability at the tbo-filgrastim injection site will be assessed at 1 hour (±30 minutes) 
following tbo-filgrastim administration on each day of administration. The site will be assessed 
for the presence and severity of pain, erythema/redness, ecchymosis, and induration.
Pain will be assessed as 0 (absent), 1 (painful on touch), 2 (painful when limb is moved), or 3 
(spontaneously painful). For erythema/redness, ecchymosis, and induration, the surface diameter 
will be recorded in mm if ≥5 mm.
3.6.7.
Spleen Sonography
A sonographic examination of the spleen will be performed at screening, on day 4 of tbo-
filgrastim treatment, at the end-of-study visit, and if the patient reports left upper abdominal 
and/or shoulder tip pain.
The investigator will assess the findings as normal, abnormal not clinically significant, or 
abnormal clinically significant.
3.6.8.
Immunogenicity Assessment
Blood will be drawn for the assessment of ADA at screening, at the end-of-study visit, and at 30 
and 90 days after the last administration of tbo-filgrastim in CTX cycle 1.
The main endpoint from the assessment will be the presence of antibodies in the sample, reported 
as positive or negative. If it is found that there are patients who receive commercial filgrastim in 
the follow-up period, extra tables and listings will be prepared for patients with and without 
commercial filgrastim usage in the follow-up part of the study.
3.7.
Follow-Up Assessments
3.7.1.
Survival Status
The status of the patient (alive/dead/lost to follow-up) will be collected at the follow-up visits at 
30 and 90 days after the last administration of tbo-filgrastim in CTX cycle 1.
3.7.2.
Immunogenicity Assessment
Blood samples will be taken for measurement of ADA at 30 and 90 days after the last 
administration of tbo-filgrastim in CTX cycle 1.
3.7.3.
Concomitant Medication
Concomitant medication taken during the follow-up period will be recorded.


Statistical Analysis Plan
Study XM02-ONC-201
21
4.
ANALYSIS POPULATIONS
4.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population will include all enrolled patients. A patient is considered 
enrolled whenthe informed consent form is signed. The set of enrolled patients includes all 
patients who were enrolled in the study, regardless of whether or not a patient took any study 
drug.
4.2.
Safety Analysis Set
The safety analysis set (SAF) will include all enrolled patients who receive at least 1 dose of 
study drug.
4.3.
Full Analysis Set
The full analysis set (FAS) will include all patients in the ITT population who receive at least 
1 dose of study drug and have at least 1 postbaseline efficacy assessment.
4.4.
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set will consist of all enrolled patients who receive at least 1 dose 
of study drug and have at least 1 evaluable pharamcokinetic parameter.


Statistical Analysis Plan
Study XM02-ONC-201
22
5.
GENERAL ISSUES FOR DATA ANALYSIS
5.1.
General Considerations
All data listings, summaries, and statistical analyses will be performed and data appendices will 
be created using SAS® system version 9.1.3 or later.
For continuous variables, descriptive statistics will be provided, showing the number of patients 
(N), number of non-missing observations (n), mean, standard deviation (SD), standard error of 
the mean (SE), median, minimum, and maximum. For categorical variables, frequency tables 
will be provided, showing the number of patients, the number of missing observations (if any), 
and the number and percentage (based on the number of non-missing observations) of patients 
falling into each category.
Summaries of clinically significant abnormal values will include all postbaseline values 
(including scheduled, unscheduled, and early termination visits).
The end-of-study time point will include patients who have withdrawn early and those who 
completed the study.
5.2.
Specification of Baseline Values
In general, unless specified otherwise, for all variables/endpoints, the last observation before the 
first administration of tbo-filgrastim will be considered as the baseline value.
5.3.
Stratification Criteria/Sub-group Analysis Sets
All summary tables will be produced by age group (1 month to <2 years, 2 to <12 years, and 12 
to <16 years) and overall for all age groups. Age group will be included in all listings.
Post-hoc, the different CTX therapy regimens received by each patient will be reviewed and 
patients will be divided into mild, moderate, and severe CTX toxicity groups based on the 
myelotoxicity of the CTX therapy they received. This classification will be done based on a 
review of literature data, and not based on the efficacy data in this study.
5.4.
Multiple Comparisons and Multiplicity
The analyses in this study will be descriptive in nature, all patients receive the same treatment, 
and no between groups comparisons will be made. Therefore there is no requirement for any 
adjustment for multiple comparisons or multiplicity.
5.5.
Handling of Withdrawals and Missing Data
For the calculation of DSN and time to ANC recovery, missing ANC values during CTX cycle 1 
will be imputed as described below. However, imputation of missing ANC values will be 
performed only if at least 3 non-missing ANC values (including the baseline value) are available.

Missing ANC values pre-CTX and pre-tbo-filgrastim dose (baseline) will not be 
imputed.


Statistical Analysis Plan
Study XM02-ONC-201
23

Missing ANC values for measurements between baseline and the last scheduled 
measurement (15 days postdose) that lie between 2 non-missing measurements will 
be imputed using linear (= straight line) interpolation.

Missing ANC values at the end (ie, after the last available measurement up to day 15) 
will be imputed using the last observation carried forward (LOCF) method.

ANC values for days 2, 3, 4, 8, 9, 11, 13, and 14 postdose (no measurements 
scheduled) will be imputed as described before, using linear interpolation or LOCF, 
as applicable.
Imputed values will be presented in the corresponding listings and flagged as such. In the 
summary statistics for ANC, missing values will not be imputed.
For all other variables, imputation of missing values is not foreseen.
5.6.
Study Days and Visit Windows
For by-visit summaries, if there are multiple assessments at a postbaseline visit, except for the 
pre-planned multiple ECG assessments, the last nonmissing assessment at that visit will be used 
for the summary. This includes assessments at the scheduled and unscheduled visits. For patients 
who withdraw from the study, data at the early termination visit will be included in the end-of-
study time point in the summaries.
Study days will be numbered relative to the first day of administration of tbo-filgrastim. The start 
of treatment (day 1) is defined as the date on which a patient takes the first dose of 
tbo-filgrastim, as recorded on the CRF. Days will be numbered relative to study start (ie, ..., –2, –
1, 1, 2, ...; with day 1 being the start of study drug and day –1 being the day before the start of 
study drug).
5.7.
Sequence of Planned Analyses
5.7.1.
Interim Analyses
No interim analysis is planned for this study.
An independent DMC will be set up to review accumulating safety data on a regular basis. 
Recruitment of patients in the youngest age stratum (1 month to <2 years) will begin only once 
safety (from the start of study to CTX-day 21) and pharmacodynamic (from the start of study to 
day 15 [relative to first tbo-filgrastim administration]) results are available for a minimum of 
6 patients in the middle age stratum and have been reviewed by the DMC and no significant 
safety signals that prevent recruitment in the youngest age stratum have been detected. The sole 
task of the DMC is to protect the patients, especially the patients in the youngest age stratum, 
from risks possibly related to the treatment with tbo-filgrastim. Therefore, no operational bias of 
the activities of the DMC on final study results is expected and the analyses prepared for the 
DMC are not regarded as interim analyses in the usual sense.
Details of the DMC will be documented in a separate DMC charter.


Statistical Analysis Plan
Study XM02-ONC-201
24
5.7.2.
Final Analyses and Reporting
The database will be locked for the final data analysis after completion of the treatment period of 
the last patient. The follow-up data will be analysed separately after completion of the follow-up 
period and lock of the respective data. Immunogenicity data will be reported only after 
completion of the bioanalytical analysis of the ADA samples collected in the follow-up period.
Any exploratory analyses completed to support study analyses, not identified in this SAP, will be 
documented and reported in appendices to the CSR.


Statistical Analysis Plan
Study XM02-ONC-201
25
6.
STATISTICAL ANALYSIS
6.1.
Study Population
6.1.1.
General
The summary of patient disposition will be produced based on all patients (ITT population). For 
all other study population tables, the safety analysis set will be used unless otherwise specified. 
Summaries will be presented by age group and overall unless otherwise specified.
6.1.2.
Patient Disposition
Patients screened, patients screened but not in the ITT population, and the reason the patients 
were not in the ITT population will be summarized only for the overall group using patient
counts. Patients in the ITT population, patients in the ITT population but not treated, patients in 
the safety analysis set and FAS, patients who completed the treatment period of the study, and 
patients who withdrew from the study will be summarized using descriptive statistics. Patients 
who withdrew from the study will also be summarized using descriptive statistics by reason for 
withdrawal. This summary will include all patients in the ITT population. The denominator for 
calculating the percentages will be the number of patients in the ITT population.
6.1.3.
Demographics and Baseline Characteristics
Patient demographic information (age, weight, height, body mass index [BMI], sex, ethnicity, 
and race) will be summarized by age group and overall. Categories for missing data will be 
provided as necessary.
If different from the safety analysis set, demographic and baseline characteristics will also be 
displayed for the FAS and the pharmacokinetic analysis set.
A summary table of the Lansky performance status at baseline will also be produced.
Demographic and baseline characteristic data will be listed.
6.1.4.
Actual Chemotherapy
The number and percentage of patients receiving each CTX therapy combination will be 
summarized by age group and CTX toxicity. Additionally, a summary will be produced showing 
the number and percentage of patients in each CTX toxicity group by age group.
Details of CTX administration including the dose and duration of CTX treatment for each 
individual patient will be listed.
6.1.5.
Medical History
Patients with a medical history assessment, patients with at least 1 abnormal medical history
finding, and medical history findings by system organ class category will be summarized using 
descriptive statistics.
Cancer history data of TNM status, tumor type, stage, and months since diagnosis will also be 
summarized using descriptive statistics.


Statistical Analysis Plan
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26
Listings will be provided of medical history and cancer history data.
6.1.6.
Prior Medications
All prior medications will be coded using the World Health Organization dictionary of medical 
codes (WHO Drug). The incidence of prior medications will be summarized using descriptive 
statistics by therapeutic class and preferred term. Patients are counted only once in each 
therapeutic class category, and only once in each preferred term category. Prior medications will 
include all medications recorded in the CRF taken prior to the first day of study drug treatment.
Prior chemotherapy and radiotherapy will be summarized separately in a similar way.
6.1.7.
Electrocardiography
The investigator’s interpretation of the ECG findings (normal, abnormal not clinically 
significant, abnormal clinically significant, and missing) at baseline will be summarized using 
descriptive statistics.
6.1.8.
Physical Examinations
Physical examinations will be performed at screening and end-of-study visits. An abnormality at 
screening will be reported as part of medical history. A summary showing the number and 
percentage of patients with normal, abnormal not clinically significant, and abnormal clinically 
significant findings at baseline will be produced.
6.1.9.
Protocol Violations
Patients with at least 1 protocol violation for each category will be summarized using descriptive 
statistics.
Protocol violations detected during the course of monitoring the study and during data cleaning 
will be recorded in the CRF and categorized as a violation of inclusion or exclusion criteria, a 
violation impacting the primary objective variable, a violation of Good Clinical Practice
guidelines, non-compliance to study medication or excluded concomitant medication/treatment.
The analysis of protocol violations will be performed with the ITT population.
6.1.10.
Childbearing Potential 
For female patients, information related to childbearing potential will be collected at the 
screening visit. This information will be listed.
6.2.
Safety Analysis
6.2.1.
General
The safety analysis set will be used for all safety analyses. Summaries will be presented by age 
group and overall unless otherwise specified.
6.2.2.
Study Drug Administration
Duration of treatment (days treated) is the number of days on treatment based on the first and last 
days of treatment with the study drug (last day of study drug – first day of study drug + 1).


Statistical Analysis Plan
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Weeks on treatment using the categories ≤1 week, >1 to ≤2 weeks, and >2 weeks will be 
summarized using descriptive statistics. Duration of treatment (days) will also be summarized 
using descriptive statistics.
In addition, the number of tbo-filgrastim administrations, the average daily dose in μg/kg/day
and the total dose received in μg/kg will be calculated and summary tables of descriptive 
statistics of these presented.
The average daily dose will be calculated as:
Total dose in μg summed over all doses / {([date of last administration –date of first 
administration] + 1) × body weight in kg}
The total dose received will be calculated as:
Total dose in μg summed over all doses / body weight in kg
Compliance will be calculated as:
(Total dose administered [μg] / total dose that should have been administered [μg]) × 100
where total dose administered is the sum of the actual dose in μg over all administrations of 
tbo-filgrastim, and total dose that should have been administered in μg is:
5 × body weight (kg) × ([date of last administration – date of first administration] + 1)
The percentage compliance will be summarized using descriptive statistics and the number and 
percentage of patients in the categories ≤80%, >80to ≤120% and >120% will be presented.
6.2.3.
Adverse Events
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Any adverse event occurring on or after the start of tbo-filgrastim administration 
and ≤ 30 days after the last dose of tbo-filgrastim is considered to be a treatment emergent 
adverse event (TEAE). All other adverse events are considered to be non-treatment emergent 
adverse events (non-TEAE). If there is any doubt due to missing or partial dates as to whether an 
adverse event is a TEAE, then it will be counted as a TEAE. AEs which started prior to first 
CTX dose will be listed but not included in the summaries of all AEs or AEs related to CTX.
An adverse event overview summary table will be provided, showing the number (and %) of 
patients with any adverse event (TEAE and non-TEAE), any TEAE, any TEAE that was judged 
as related to tbo-filgrastim, any TEAE with toxicity grade ≥3, any TEAE that was judged as 
related to tbo-filgrastim with toxicity grade ≥3, any serious TEAE, any serious TEAE that was 
judged as related to tbo-filgrastim, any TEAE leading to discontinuation, any TEAE that was 
judged as related to tbo-filgrastim leading to discontinuation, any TEAE leading to death, and 
any TEAE that was judged as related to tbo-filgrastim leading to death.
In addition, summaries will be presented for all AEs, all TEAEs (overall and by toxicity grade),
TEAEs judged as related to tbo-filgrastim (overall and by toxicity grade), AEs related to CTX, 
serious TEAEs, any serious TEAEs judged as related to tbo-filgrastim, TEAEs and TEAEs 
judged as related to tbo-filgrastim causing discontinuation from the study, and non-serious 
TEAEs. The incidence of these TEAEs will be summarized using descriptive statistics by system 
organ class and preferred term. Patients are counted only once in each system organ class 


Statistical Analysis Plan
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category, and only once in each preferred term category. Treatment-related TEAEs are those 
considered by the investigator to have a reasonable possibility of being treatment-related. Any 
adverse event with a missing relationship to study drug will be considered to be 
treatment-related. For the summaries by toxicity grade, patients are counted at the greatest 
toxicity grade. If a TEAE is missing the flag indicating whether it is serious it will be excluded 
from the summary of serious TEAEs but included in the summary of non-serious TEAEs.
Follow-up adverse events are defined as those with an onset date >30 days after the last dose of 
tbo-filgrastim. The incidence of follow-up AEs will be summarized using descriptive statistics 
by system organ class and preferred term.
Listings for deaths, serious adverse events, adverse events leading to discontinuation, MedDRA 
dictionary terms for adverse event descriptions, and adverse event preferred terms by patient 
number will be presented.
6.2.4.
Deaths
If any patient dies during the study, a listing of deaths will be provided. All relevant information,
including number of days after last study drug administration and whether or not a patient 
received commercial filgrastim in the follow-up period, will be discussed in the patient’s 
narrative included in the CSR. 
6.2.5.
Clinical Laboratory Tests
Summary statistics for serum chemistry and hematology laboratory tests will be presented at 
baseline and end-of-study. Laboratory tests results and changes from baseline to end-of-study
will be summarized using descriptive statistics.
For all laboratory parameters the results will be classified as low, normal or high according to the 
respective laboratory normal range. In addition, the results will be classified into three categories 
of normal (grade 0), grade 1 or 2, and grade ≥3, according to NCI CTCAE version 4.03. Shifts 
from baseline to end-of-study will be summarized using patient counts for the two sets of 
categories for laboratory parameters. 
The following laboratory parameters will be graded according to the NCI CTCAE version 4.03:

Hematology: hemoglobin, platelets, WBC, ANC, and absolute lymphocyte count

Serum chemistry: ALT, AST, bilirubin, alkaline phosphatase, GGT, glucose, uric 
acid, creatinine, sodium, potassium, and phosphate.
For these parameters, results with grade ≥3 will be regarded as potentially clinically significantly 
abnormal. The incidence of potentially clinically significantly abnormal results will be 
summarized for laboratory data using descriptive statistics.
All laboratory values recorded during the study will be individually listed and values outside 
reference ranges flagged.
Listings for clinically significant abnormal laboratory data will be presented.
In addition, results of urine pregnancy tests and urine drug screen will be listed.


Statistical Analysis Plan
Study XM02-ONC-201
29
6.2.6.
Vital Signs
Summary statistics for vital signs will be presented at each time point measured (see Table 1). 
Vital signs values and changes from baseline to each postbaseline time point will be summarized 
using descriptive statistics. The incidence of potentially clinically significantly abnormal values 
will be summarized for selected vital signs using descriptive statistics. In the summary tables, 
sitting or supine vital sign results will be combined.
Table 3 specifies the criteria for identifying vital signs as potentially clinically significantly
abnormal.
Table 3:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Systolic blood pressure
n/a
Change of 20 mmHg
Diastolic blood pressure
n/a
Change of 15 mmHg
Pulse
n/a
Change of 15 beats/min
Respiration Rate
n/a
Change of 8 breaths/min
Body temperature
≥38.0C
A listing of all vital sign data will be produced, and a separate listing for potentially clinically 
significant abnormal vital signs will also be provided.
6.2.7.
Electrocardiography 
Shifts in ECG interpretation (normal, abnormal not clinically significant, and abnormal clinically 
significant) from baseline to each time point where ECGs are recorded (see Section 3.6.4) and 
overall will be summarized using patient counts. This will be done separately for both the 
investigator’s and central reader’s interpretation. For each time point, the worst case out of the 
available assessments at that time point will be used. For overall, the worst postbaseline finding 
(the abnormal finding if there are both normal and abnormal findings) for the patient will be 
summarized.
Summary statistics for numeric ECG parameters will be presented at baseline and each time 
point where they are recorded. Before summary statistics are calculated, triplicate ECG readings 
will be averaged within subjects. Electrocardiogram parameter results and changes from baseline 
to each postbaseline visit will be summarized using descriptive statistics. 
In addition, a summary table showing the number and percentage of patients with potentially 
clinically significant abnormal values will be presented by time point. Values for QTcB and 
QTcF will be summarized using the following categories:

≤450 ms

>450 – 480 ms

>480 – 500 ms

>500 ms


Statistical Analysis Plan
Study XM02-ONC-201
30
Changes from baseline will be summarized using the categories no increase or increase ≤30 ms, 
increase >30 to 60 ms, and increase >60 ms.
ECG parameter results will be listed, as will ECG findings from both the investigator’s and 
central reader’s interpretations.
6.2.8.
Physical Examinations
Shifts in physical examination findings (normal, abnormal not clinically significant, and 
abnormal clinically significant) from baseline to end-of-study for each body system will be 
summarized using patient counts.
Results from physical examinations will be listed. Details of clinically significant findings will 
be captured in the medical history or adverse event tables and listings as applicable.
6.2.9.
Local Tolerability Assessments
Evaluation of local tolerability at the tbo-filgrastim injection site will be based on the presence 
and severity of pain, erythema/redness, ecchymosis, and induration at the injection site following 
each administration of tbo-filgrastim.
The incidence (and severity for pain) of these reactions will be summarized by means of 
frequency tables, and individual patient data will be listed.
6.2.10.
Spleen Sonography
Results from spleen sonography assessments (normal, abnormal not clinically significant, and 
abnormal clinically significant) will be summarized by means of a shift table showing the shift 
from baseline to day 4 of tbo-filgrastim administration and end-of-study assessment.
The spleen sonography results will be listed, and clinically significant findings will be 
summarized in the context of summaries for medical history and adverse events.
6.2.11.
Immunogenicity
Immunogenicity results will be analysed by comparing sample status at all postdose time points 
(including follow-up time points) to that of predose to determine treatment-induced ADA 
response. If both postdose and predose samples are positive, titer values will be compared to 
determine treatment-boosted ADA response (ie, titer increased by 4 folds). The immunogenicity 
results will be presented in a separate report.
6.2.12.
Concomitant Medication
Medications will be divided into three distinct categories: prior, concomitant, and concomitant 
during follow-up. Prior medications are medications that started and ended before the first 
administration of tbo-filgrastim in the study. Concomitant medications during the follow-up are 
defined as those with a start date after the day of last tbo-filgrastim administration in the study. 
All other medications will be regarded as concomitant medications. Prior medications, 
concomitant medications, and concomitant medications during follow-up will be reported in 
separate tables.
Concomitant medications do not include CTX.


Statistical Analysis Plan
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31
All prior medications, concomitant medications, and concomitant medications during the follow-
up will be coded using the WHO Drug Dictionary (Version WHODRUG 2014Mar01DDE).
Their incidences will be summarized using descriptive statistics by therapeutic class (ATC level 
2) and preferred term. Patients are counted only once in each therapeutic class category, and only 
once in each preferred term category.
Details of concomitant medications will be listed. A special patient listing of patient who 
received commercial filgrastim in the follow-up period will be prepared.
6.3.
Pharmacokinetic Analysis
6.3.1.
General
The pharmacokinetic analysis set will be used for all pharmacokinetic analyses. Summaries will 
be presented by age group and overall, and by CTX toxicity group and overall unless otherwise 
specified.
6.3.2.
Summary of Drug Concentration Data
Descriptive statistics will be produced for the serum tbo-filgrastim concentration values by time 
point, including mean, SD, geometric mean (GM), coefficient of variation (CV), minimum and 
maximum values, and 95% confidence interval (CI) for the GM. Nominal times will be used for 
these descriptive statistics. Serum concentrations for tbo-filgrastim below the quantifiable limit 
(BQL) will be set to zero in the computation of mean concentration values. If over half of the 
patients in a given summary table entry have values BQL then the descriptive statistics will not 
be presented and will instead display as BQL for the mean and missing for all other statistics.
The values for each individual patient will be listed, and values used in the summary statistics 
will be provided in the listings. Figures will be produced showing the individual time profiles (1 
patient per page) on a linear and semi-log scale, and GM values by age group on a linear and 
semi-log scale. The GM plots will be by scheduled sampling time and will show time in hours. 
These plots will match the summary table results and will not have an observation at a given 
time point if more than half of the patients have values BQL. The individual patient plots will be 
by actual sampling time and will show time in hours. These plots will use the BQL handling 
procedure described in Section 6.3.3.
6.3.3.
Calculation of Pharmacokinetic Parameters
Calculation of pharmacokinetic parameters will be done by standard non-compartmental analysis
which will include observational parameters such as Cmax and Tmax, and in addition AUC,
percentage of AUC extrapolated, t½, λz, CL/F, and Vz/F. AUC parameters will be calculated 
using linear trapezoidal method. These parameters will be derived, as described in Table 4:
Table 4:
Derivation of Pharmacokinetic Parameters
Parameter
Description
SAS Programming 
Notes
Cmax
Maximum serum concentration. Observed peak tbo-filgrastim 
concentration obtained directly from the experimental data 
without interpolation, expressed in concentration units
Cmax from WNL


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Study XM02-ONC-201
32
Parameter
Description
SAS Programming 
Notes
Tmax
Time to Cmax. First observed time to reach peak tbo-filgrastim
concentration obtained directly from the experimental data 
without interpolation, expressed in time units.
Tmax from WNL
AUClast
Area under the concentration-time curve (time 0 to time of last 
quantifiable concentration)
AUClast from WNL
AUC0-12
Area under the concentration-time curve (time 0 to 12 hours
postdose)
AUC(0-12) from WNL
AUC0-inf
Area under the serum concentration-time curve (time 0 to 
infinity), calculated as AUCinf = AUClast+ Clast/ λz, where 
Clast is the last measurable tbo-figrastim concentration and λz
is the terminal elimination rate constant, expressed in inverted 
units of time. Percent extrapolation less than or equal to 20% 
is required to retain AUCinf and associated parameters (λz, 
t1/2).
AUCINF_obs from WNL
If AUC_%Extrap_obs 
>20% then parameter is 
deleted
%AUCext
Percentage of the AUC that is due to the extrapolation
%AUCext = ([AUCinf –
AUClast]/AUCinf) * 100
λz
Terminal elimination rate constant calculated by linear 
regression of the terminal log-linear portion of the 
concentration-time curve. Linear regression of at least three 
points and an r2 > 0.80 are required to retain λz and all 
associated parameters (t1/2).
Lambda_z from WNL
If Rsq ≤ .80 then 
parameter is deleted
t½
Terminal half-life, calculated as ln(2)/ λz , expressed in time 
units. At least 3 concentrations in the terminal phase are
required to retain t1/2. Percent extrapolation less than or equal 
to 20% and r2 > 0.80 is required to retain t1/2.
HL_Lambda_z from 
WNL
If AUC_%Extrap_obs 
>20% or Rsq ≤ .80 then 
parameter is deleted
CL/F
Apparent clearance, expressed in volume / time unit. r2 > 0.80 
and percent extrapolation ≤20% are required to retain CL/F.
Cl_obs from WNL
If Rsq ≤ .80 or 
AUC_%Extrap_obs >20% 
then parameter is deleted
Vz/F
Apparent volume of distribution, expressed in volume unit. r2
> 0.80 and percent extrapolation≤20% are required to retain 
CL/F.
Vz_obs from WNL
If Rsq ≤ .80 or 
AUC_%Extrap_obs >20% 
then parameter is deleted
The pharmacokinetic parameters will be estimated from the concentration-time profiles for all 
subjects in the pharmacokinetic analysis set. In estimating the pharmacokinetic parameters, BQL 
values at the beginning of the profile will be set to zero. BQL values that occur after the first 
quantifiable point will be considered missing. Values that are embedded between BQLs, or 
quantifiable values occurring after 2 or more BQLs, will be set to missing at the discretion of the 
pharmacokineticist. Actual sampling times, rather than scheduled sampling times, will be used in 
all computations involving sampling times. If the actual time or dose time is missing, the 
scheduled time may be substituted in order to calculate the pharmacokinetic parameter.


Statistical Analysis Plan
Study XM02-ONC-201
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6.3.4.
Statistical Analyses of Pharmacokinetic Parameters
All pharmacokinetic parameters (Cmax, AUClast, AUC0-12, AUC0-inf, percentage of AUC 
extrapolated, t½, λz, CL/F and Vz/F) will be summarized by age group and in addition by CTX 
toxicity group using the standard summary statistics including the mean, SD, GM, CV for the 
GM, minimum and maximum values, and the 95% CI for the GM. All Tmax values will be 
summarized by age group using mean, SD, median, and minimum and maximum values.
The pharmacokinetic data from this study may also be combined with pharmacokinetic data from 
other studies as part of a larger-scale population pharmacokinetic analysis for tbo-filgrastim. The 
results of any population pharmacokinetic analysis will be reported separately from the CSR for 
XM02-ONC-201. 
6.4.
Pharmacodynamics Analysis
6.4.1.
Calculation of Pharmacodynamics Parameters
The following table shows how each of the ANC-related pharmacodynamic parameters will be 
derived. All of these will be based on actual sampling times, and will only be calculated for 
patients with at least 3 non-missing ANC measurements during CTX cycle 1 prior to imputing 
missing data.
Note that if a day 15 ANC measurement is not available, but a CTX-day 21 ANC value is 
available, and the date of this sample corresponds to day 15, then the CTX day 21 ANC value 
will be used as the day 15 ANC value.
Table 5:
Derivation Method for Pharmacodynamics Parameters
Parameter
Derivation Method
Incidence of severe neutropenia
Any value of ANC <0.5 × 109/L at any time.
DSN
Derived by counting the number of days with ANC values <0.5 ×
109/L, with missing days imputed as described in Section 5.5 prior to 
counting.
AUCANC
AUC from Day 1 to Day 15, calculated using the linear trapezoidal 
rule. Missing ANC values will not be imputed.
ANC nadir
The lowest observed ANC value observed from Day 1 to Day 15 
(measured in 109/L).
ANCmax
The highest observed ANC value observed from Day 1 to Day 15 
(measured in 109/L).
Time to ANC nadir from the 
first tbo-filgrastim 
administration up to the 
occurrence of the ANC nadir
Day of ANC nadir (first occurrence) – day of first tbo-filgrastim 
administration.
Time to ANC nadir from the 
first CTX administration up to 
the occurrence of the ANC 
nadir
Day of ANC nadir (first occurrence) – day of first CTX administration.


Statistical Analysis Plan
Study XM02-ONC-201
34
Parameter
Derivation Method
Time to ANC recovery to 
≥1.0 × 109/L from ANC nadir 
Day of ANC recovery – day of ANC nadir (first occurrence).
Day of ANC recovery is first occurrence of ANC ≥1.0 × 109/L after 
the first value which is <1.0 × 109/L.
If the day of ANC recovery is before the day of nadir, then the day of 
ANC recovery is set as the first occurrence of ANC ≥1.0 × 109/L after 
the nadir.
If no ANC value <1.0 × 109/L, then time to recovery will be set to 0.
Missing ANC values will be imputed as described in Section 5.5.
If no ANC value ≥1.0 × 109/L after the first value which is <1.0 ×
109/L, then the date of the CTX Day 21 visit will be used as the day of 
recovery.
Time to ANC recovery to 
≥2.0 × 109/L from ANC nadir
Day of ANC recovery – day of ANC nadir (first occurrence).
Day of ANC recovery is first occurrence of ANC ≥2.0 × 109/L after 
the first value which is <2.0 × 109/L.
If the day of ANC recovery is before the day of nadir, then the day of 
ANC recovery is set as the first occurrence of ANC ≥2.0 × 109/L after 
the nadir.
If no ANC value <2.0 × 109/L, then time to recovery will be set to 0.
Missing ANC values will be imputed as described in Section 5.5.
If no ANC value ≥2.0 × 109/L after the first value which is <2.0 ×
109/L, then the date of the CTX Day 21 visit will be used as the day of 
recovery.
Time to ANC recovery to 
≥1.0 × 109/L from the first
tbo-filgrastim administration
Similar to time to ANC recovery to ≥1.0 × 109/L from ANC nadir, 
replacing day of ANC nadir with day of first tbo-filgrastim 
administration.
Time to ANC recovery to 
≥2.0 × 109/L from the first
tbo-filgrastim administration
Similar to time to ANC recovery to ≥2.0 × 109/L from ANC nadir, 
replacing day of ANC nadir with day of first tbo-filgrastim 
administration.
Time to ANC recovery to 
≥1.0 × 109/L from CTX-day 1
Similar to time to ANC recovery to ≥1.0 × 109/L from ANC nadir, 
replacing day of ANC nadir with day of first CTX administration.
Time to ANC recovery to
≥2.0 × 109/L from CTX-day 1
Similar to time to ANC recovery to ≥2.0 × 109/L from ANC nadir, 
replacing day of ANC nadir with day of first CTX administration.
ANC= absolute neutrophil count; AUC= area under the concentration-time curve.
6.4.2.
Statistical Analyses of Pharmacodynamics
All summaries and analyses of pharmacodynamics will be done using the FAS. Summaries and 
analyses will be presented by age group and overall, and in addition by CTX toxicity group and 
overall, unless otherwise specified. All ANC values and the derived pharmacodynamic
parameters will be listed.


Statistical Analysis Plan
Study XM02-ONC-201
35
Incidence of severe neutropenia will be summarized by number and percent of patients 
experiencing severe neutropenia. 95% exact CI for the proportion experiencing severe 
neutropenia will be presented. Descriptive statistics will be produced for all other 
pharmacodynamic parameters defined in Section 6.4.1. For AUCANC, these summaries will show 
GM, CV, and 95% CI for the GM.
For DSN, AUCANC, ANCmax, ANC nadir, and the time to ANC nadir and time to ANC recovery 
variables, the influence of age group will be explored using analysis of variance (ANOVA with 
possible heteroskedasticity) with age category as a factor in the model. The least squares mean 
(LSMean) estimate and 95% CI for the LSMean for the pharmacodynamic parameter for each 
age group will be presented. In addition, pairwise LSMean differences among age groups along 
with 95% CI for these differences will be estimated. This analysis will be repeated using sex, 
type of cancer, and CTX toxicity group as factors in the model instead of age group in separate 
analyses. For AUCANC, the log-transformed value will be used in the model, and back-
transformed LSMeans and 95% CIs will be presented in the table.
Descriptive statistics will be produced of the ANC values by time point, including 95% CI for 
the mean. Nominal times will be used for these descriptive statistics, and they will be based on 
observed values (no imputation of missing values).
Plots of individual ANC values over time will be produced, on both linear and semi-log scales.
In addition, plots of mean and median values over time (nominal time point) will be produced by 
age group and CTX toxicity group.
6.5.
Efficacy Analysis
6.5.1.
General
The FAS will be used for all efficacy analyses. Summaries will be presented by age group and 
overall, and in addition by CTX toxicity group and overall, unless otherwise specified.
6.5.2.
Key Efficacy Variable and Analysis
The key efficacy variable is the incidence of FN, as defined in Section 3.5. This will be 
summarized by a frequency table along with 95% exact CI for the incidence rate, by age group
and overall, and by CTX toxicity group and overall. Logistic regression analyses with age class 
and CTX toxicity group will be performed in separate models. Out of these logistic regression 
analyses, pair-wise odds ratios along with 95% CIs for the classes of the explanatory variables 
will be estimated.
6.5.3.
Additional Efficacy Variable and Analysis
The incidence of hospitalization due to febrile neutropenia will be descriptively summarized by 
number and percent of patients experiencing hospitalization. Exact 95% CIs for the proportion 
experiencing hospitalization will be presented. In case of hospitalization, the duration of 
hospitalization and the duration in intensive care units will be descriptively analysed.
The administration of systemic antibiotics and antipyretics will be summarized by number and 
percent of patients along with 95% exact CIs for the proportion of patients experiencing either 
event.


Statistical Analysis Plan
Study XM02-ONC-201
36
6.6.
Follow-Up Data
The safety analysis set will be used for all summaries of follow-up data. Summaries will be 
presented by age group and overall, and by type of cancer and overall unless otherwise specified.
6.6.1.
Survival Status
The status of the patient (alive/dead/lost to follow-up) at the follow-up visits at 30 and 90 days 
from last tbo-filgrastim administration in CTX cycle 1 will be summarized by the number and 
percentage of patients in each category.
The status at each follow-up visit will be listed. In addition a listing will be prepared showing 
important baseline information (sex, age, type of cancer, CTX toxicity group), the information of 
whether or not the patient received commercial filgrastim during the follow-up period, the date 
of the first application of tbo-filgrastim within the study, the date of last contact/death, the 
number of days between date first tbo-filgrastim administration and date of last contact/death, 
and the last status (alive/dead/lost to follow-up).
6.6.2.
Immunogenicity Assessments
To determine treatment-induced ADA response shift tables will be prepared for the 
immunogenicity results to compare the sample status at all postdose time points (including 
follow-up time points) to that of predose. If both postdose and predose samples are positive, titer 
values will be compared by individual patient listings to determine treatment-boosted ADA 
response (ie, titer increased by 4 folds).
The shift table will be repeated separately for those patients who received commercial filgrastim 
during the follow-up period, and those who did not. The listing of immunogenicity results in the 
follow-up period will also include whether the patient received commercial filgrastim during the 
follow-up period.
6.6.3.
Concomitant Medication during Follow-Up
Concomitant medications during follow-up are defined in Section 6.2.12.
These will be coded and summarized in the same way as the prior and the concomitant 
medications during the treatment period as described in Section 6.2.12. Concomitant medications 
during follow-up will be identified in the listings. A special individual patient listing will be 
prepared for all patients who received commercial filgrastim in the follow-up period.


Statistical Analysis Plan
Study XM02-ONC-201
37
7.
CHANGES TO PROTOCOL SPECIFIED ANALYSES
The following pharmacokinetic parameters not specified in the protocol have been added:

AUClast

z

CL/F

Vz/F

% AUCinf extrapolated
In addition, the pharmacodynamic parameter of ANCmax was added.
Additional efficacy variables of incidence of hospitalization, duration of hospitalization, duration 
of stay in intensive care units, and administration of systemic antibiotics and antipyretics were 
added.


Statistical Analysis Plan
Study XM02-ONC-201
38
8.
REFERENCES
Not applicable


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