Clinical trial NCT02650193
Conditions: Non-metastatic Breast Cancer
Keywords: HSP-130 Phase 1-2 Study in patients with Breast cancer
Sponsor: Pfizer
Start date: 2015-12-01; Completion date: 2017-10-01
Enrollment: 25 participants; Allocation: ; Intervention model: PARALLEL

Brief summary:
This is a study of how one or more injections of HSP-130 under the skin effect the white blood cell counts and drug levels in women with breast cancer that has not spread to distant sites in the body (non-metastatic). This will be studied in women before breast surgery or while receiving chemotherapy. Safety will also be studied.

Additionally, the purpose of this study is to evaluate the effects and safety of single and multiple doses of HSP-130 in subjects with non-metastatic breast cancer. This study will determine the dose to move forward for future clinical trials.

Detailed description:
This is an open-label, sequential enrollment study characterizing the pharmacodynamic (PD), pharmacokinetic (PK) and safety of HSP-130 in subjects with non-metastatic breast cancer who have not previously received chemotherapy at any point prior to enrollment in this study (ZIN-130-1504).

The purpose of this study is to evaluate the effects and safety of single and multiple doses of HSP-130 in subjects with non-metastatic breast cancer. This study will determine the dose to move forward for future clinical trials.

There are two aspects of the study. In the initial part of the study, 6 subjects will be sequentially enrolled to receive HSP-130 treatment (3 mg , or 6 mg by subcutaneous injection) during the period between biopsy and definitive surgery. This will determine whether 3 mg and 6 mg have similar or different effects on the PD variables (absolute neutrophil counts and CD34+ cell counts). This part of the study is referred to as Cycle 0 since study subjects will receive no chemotherapy while receiving HSP-130 until the effect of HSP-130 on the PD variables is known. A total of 12 subjects may be enrolled in Cycle 0.

The objective of Cycle 1-4 is to determine the dose to be taken forward to Phase 3 clinical trials. Cycles 1-4 subjects will receive HSP-130 after their definitive breast surgery at the time they receive TAC chemotherapy (docetaxel, doxorubicin, and cyclophosphamide). Subjects will receive up to 4 cycles of every 3 week TAC chemotherapy with HSP-130 given on Day 2 of the chemotherapy regimen.

* If the 3 mg dose is found to be inferior (potentially subtherapeutic) to the 6 mg dose in Cycle 0, only the 6 mg dose will be studied in Cycles 1-4 (n=12), when subjects receive concomitant chemotherapy.
* If the 3 mg dose is found to be comparable to the PD results obtained in Cycle 0 with 6 mg, the 3 mg dose (n=12) will also be studied in women receiving TAC chemotherapy.

Data from the HSP-130 6 mg regimen (plus 3 mg, as appropriate) will be analysed, discussed with the FDA and determination if a dose greater than 6 mg is appropriate to study (e.g., 12 mg). If all three doses are studied, a total enrollment of up to 36 subjects is projected for Cycles 1-4.

Arms: arm 1: Cycle 0:

Regimen A: HSP 130, 3 mg, single SC injection in the deltoid region (n = 6) Regimen B: HSP 130, 6 mg, single SC injection in the deltoid region (n = 6)

Cycles 1-4:

Regimen B (n = 12): HSP 130, 6 mg, single SC injection in the deltoid region, at least 24 hours after administration of chemotherapy in Cycle 1, Cycle 2, Cycle 3, and Cycle 4.

Potential Regimen A (n = 12): 3 mg with background chemotherapy: Inclusion of this cohort will be based on assessment of comparability between Regimens A and B in Cycle 0 for ANC and CD34+ as defined above. If performed, this regimen will be HSP 130, 3 mg, single SC injection in the deltoid region, at least 24 hours after administration of chemotherapy in Cycle 1, Cycle 2, Cycle 3, and Cycle 4, as appropriate.

Conditional Regimen C (12 mg):This cohort will not be initiated until data from cycle 0 for 3 mg and 6 mg and Cycles 1-4 for 6 mg has been reviewed and analyzed.
Interventions: intervention 1: HSP-130
Intervention descriptions: intervention 1: Dosage will vary per each cohort: (Five independent cohorts) Cycle 0 Regimen A - 3 mg Cycle 0 Regimen B - 6 mg Cycles 1-4 Regimen B - 6 mg Cycles 1-4 Regimen A (Potential)- 3 mg Cycles 1-4 Regimen C (Conditional)- 12 mg

Protocol documents:
Prot_000.pdf: 
Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
ZIN-130-1504 
A Phase 1-2 ascending dose study to assess the 
pharmacodynamics, pharmacokinetics, and safety of 
HSP-130 in subjects with non-metastatic breast cancer 
following single-dose and multiple-dose administration by 
subcutaneous injection 
IND Number 
124793 
EudraCT Number 
2015-002057-35 
Sponsor 
Hospira, Inc. (Hospira) 
 
Hospira, Inc. 
275 North Field Drive 
Lake Forest, IL 60045 
Original Protocol v 2.0 
31 July 2015 
Amendment#2, Protocol v 3.0 
22 December 2015 
 
 
 
 
Page 1 of 145 
 


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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
 
INVESTIGATOR SIGNATURE PAGE 
The signature below constitutes approval of this protocol and provides the necessary 
assurance that this study will be conducted at his/her investigational site according to all 
stipulations of the protocol including all statements of confidentiality and in accordance with 
ICH GCP and local regulatory requirements. 
Address of 
Institution/Site: 
 
__________________________________________________ 
__________________________________________________ 
__________________________________________________ 
 
Telephone Number: 
 
Signed: 
 
Print Name and 
Title: 
 
Date: 
 
 
 
 
 
Page 3 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
CONTENTS 
SIGNATURE PAGE .................................................................................................................2 
INVESTIGATOR SIGNATURE PAGE ...................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ....................................................9 
PROTOCOL SYNOPSIS ........................................................................................................11 
PRINCIPAL CONTACTS .......................................................................................................22 
1 
BACKGROUND AND RATIONALE ............................................................................34 
1.1 
Background to the Disease .....................................................................................34 
1.2 
Investigational Medicinal Products........................................................................38 
1.3 
Non-clinical Data ...................................................................................................38 
1.4 
Clinical Experience ................................................................................................38 
1.5 
Rationale for the Study ..........................................................................................38 
1.5.1 
Design Features ............................................................................................38 
1.5.2 
Study Population ..........................................................................................40 
1.5.3 
Dosing Regimen and Treatment Duration ...................................................40 
1.5.4 
Selection of Pharmacodynamic Endpoints ..................................................40 
1.5.5 
Selection of Pharmacokinetic Endpoints .....................................................41 
1.6 
Risk/Benefit ...........................................................................................................42 
2 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................43 
2.1 
Primary Objectives and Endpoints.........................................................................43 
2.1.1 
Primary Objective (s) ...................................................................................43 
2.1.2 
Pharmacodynamic Endpoints .......................................................................43 
2.2 
Secondary Objectives and Endpoints.....................................................................44 
2.2.1 
Secondary Objective (s) ...............................................................................44 
2.2.2 
Pharmacokinetic Endpoints .........................................................................44 
2.3 
Safety Variables .....................................................................................................45 
2.4 
Anti-HSP-130 Antibody Assessment ....................................................................46 
2.5 
Additional Assessments .........................................................................................46 
2.5.1 
Performance Status ......................................................................................46 
2.5.2 
Clinical Index of Stable Febrile Neutropenia ..............................................47 
2.5.3 
Functional Assessment of Cancer Therapy – Neutropenia ..........................48 
3 
INVESTIGATIONAL PLAN ..........................................................................................49 
3.1 
Study Design ..........................................................................................................49 
3.2 
Number of Sites and Subjects ................................................................................51 
3.3 
Estimated Study Duration ......................................................................................51 
4 
STUDY POPULATION SELECTION ...........................................................................53 
4.1 
Study Population ....................................................................................................53 
4.2 
Inclusion Criteria ...................................................................................................53 
 
Page 4 of 145 
 


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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
6.5 
Measurement Methods ...........................................................................................70 
6.5.1 
Pharmacodynamic Assay .............................................................................70 
6.5.2 
Pharmacokinetic Assay ................................................................................70 
6.5.3 
Antibody Assay ............................................................................................71 
6.5.4 
Sample Analysis Repeats .............................................................................71 
6.6 
Subject Enrollment.................................................................................................71 
6.7 
Subject Replacement ..............................................................................................71 
7 
WITHDRAWAL AND EARLY DISCONTINUATION ................................................72 
7.1 
Early Discontinuation of the Study ........................................................................72 
7.2 
Early Discontinuation of Individual Subjects ........................................................72 
8 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING .........................74 
8.1 
Definitions..............................................................................................................74 
8.1.1 
Adverse Event ..............................................................................................74 
8.1.2 
Adverse Events of Special Interest ..............................................................74 
8.1.3 
Serious Adverse Events ...............................................................................75 
8.1.4 
Suspected Unexpected Serious Adverse Reaction .......................................76 
8.2 
Adverse Event Severity..........................................................................................76 
8.3 
Causality of Adverse Events ..................................................................................76 
8.4 
Adverse Event Collection Period ...........................................................................77 
8.5 
Serious Adverse Event Reporting ..........................................................................77 
8.6 
Pregnancy ...............................................................................................................78 
9 
PROTOCOL DEVIATIONS ...........................................................................................79 
10 STATISTICAL CONSIDERATIONS.............................................................................80 
10.1 
Statistical Methods .................................................................................................80 
10.1.1 
Subject Population/Data Sets to be Evaluated .............................................80 
10.1.2 
Sample Size Determination..........................................................................80 
10.1.3 
Data and Interim Analyses ...........................................................................80 
10.1.4 
Handling of Missing Data ............................................................................80 
10.2 
Statistical Analyses ................................................................................................81 
10.2.1 
Subject Disposition and Demography .........................................................81 
10.2.2 
Assessment of Efficacy ................................................................................81 
10.2.3 
Assessment of Pharmacodynamics and Pharmacokinetics ..........................81 
10.2.4 
Additional Assessments ...............................................................................82 
10.2.5 
Assessment of Safety ...................................................................................82 
10.2.6 
Deaths ..........................................................................................................84 
11 REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS .......................................85 
11.1 
Declaration of Helsinki ..........................................................................................85 
11.2 
Good Clinical Practice ...........................................................................................85 
 
Page 6 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
11.3 
Ethical Approval ....................................................................................................85 
11.3.1 
Initial Approval ............................................................................................85 
11.3.2 
Approval of Amendments ............................................................................85 
11.3.3 
End of Trial Notifications ............................................................................85 
11.4 
Regulatory Authority Approval .............................................................................85 
11.5 
Other Required Approvals .....................................................................................86 
11.6 
Insurance ................................................................................................................86 
11.7 
Pre-study Documentation Requirements ...............................................................86 
11.8 
Informed Consent...................................................................................................86 
11.9 
Contact with General Practitioner ..........................................................................86 
11.10 Subject Confidentiality ..........................................................................................86 
11.11 Data Protection.......................................................................................................87 
11.12 Study Documentation and Data Storage ................................................................87 
11.13 Disclosure of Information ......................................................................................87 
11.14 Publication .............................................................................................................88 
12 ADMINISTRATIVE OBLIGATIONS ...........................................................................89 
12.1 
Source Data Access................................................................................................89 
12.2 
Language ................................................................................................................89 
12.3 
Data Collection ......................................................................................................89 
12.4 
Monitoring .............................................................................................................90 
12.5 
Independent Data Monitoring Committee .............................................................90 
12.6 
Quality Control and Quality Assurance .................................................................90 
13 REFERENCES ................................................................................................................91 
14 APPENDICES .................................................................................................................95 
Appendix A. 
Responsibilities of the Clinical Investigator ......................................96 
Appendix B. 
Documents Required Prior to Initiation of the Study ........................97 
Appendix C. 
Elements of the Informed Consent Form ...........................................98 
Appendix D. 
Declaration of Helsinki ....................................................................100 
Appendix E. 
Adverse Events – Categorized as SAEs...........................................105 
Appendix F. 
Neulasta® (pegfilgrastim, Amgen) Summary of Product 
Characteristics ......................................................................................................107 
Appendix G. 
Protocol Amendment Complete Listing of Changes .......................108 
Appendix H. 
Neulasta® (pegfilgrastim, Amgen) Package Insert ..........................145 
 
 
 
 
Page 7 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Study Activities: Cycle 0: 3 mg or 6 mg SC Injection (s) 
Without Background Chemotherapy ...........................................................................24 
Table 2. 
Schedule of Study Activities: Cycles 1 and 4 for Subjects Receiving 
6 mg or 12 mg¥ SC Injection(s) 24 hours Post-Chemotherapy Administration 
Each Cycle* .................................................................................................................26 
Table 3. 
Schedule of Study Activities: Cycles 2 and 3 for Subjects Receiving 
6 mg or 12 mg¥ SC injection(s) 24 hours Post-Chemotherapy Administration Each 
Cycle* 
....................................................................................................................29 
Table 4. 
Factors to Consider in Assessing Risk of a Febrile Neutropenic 
Episode in Patients Undergoing Cytotoxic Chemotherapy for Malignancy ................35 
Table 5. 
The WHO/Zubrod/ECOG Scale ................................................................46 
Table 6. 
Outcomes by CISNE by Risk Categories (n = 1,133) ...............................48 
Table 7. 
Composition of Formulations of HSP-130 ................................................57 
Table 8 Clinical Laboratory Tests ......................................................................................63 
 
LIST OF IN-TEXT FIGURES 
Figure 1  
Study Design Schematic ............................................................................23 
 
 
 
 
Page 8 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
The main reasons for this amendment are as follows (a complete listing of changes [except 
minor typographical errors] can be found in Appendix G. 
• The Protocol version and the Protocol Date have been updated for accuracy 
• Updated the Signature Page to provide information on the new Global Medical 
Director, Pharmacovigilance and Safety 
• Removed the docetaxel and cyclophosphamide (TC) regimen in the following 
sections: Synopsis (Study Design) and Section-1.5.1 (Design Features) 
• Modified the study population in the following sections: Synopsis (Study Design); 
Section-1.5.1 (Design Features); Section-1.5.2 (Study Population), Section-1.6 
(Risk/Benefit) and Section-3.1 (Study Design) 
• Removed TC regimen in the following sections: Synopsis (Study Design, Key 
Inclusion Criteria for all study subjects, Key Exclusion Criteria), Section-4.2 
(Inclusion Criteria) and Section-4.3 (Exclusion Criteria) 
• Modified the chemotherapy cycle duration in the following sections: Synopsis 
(Duration of Treatment, Safety Assessments), Section-1.5.3 (Dosing Regimen and 
Treatment Duration), Section-2.3 (Safety Variables) and Section-3.3 (Estimated 
Study Duration) 
• Changes were made to the total blood volume collected and their breakdown during 
the study in the following sections: Synopsis (Pharmacodynamics and 
Pharmacokinetics of HSP-130; Pharmacodynamic Sampling/Collection); Section-
6.2.12 (Total blood volume to be collected during the study) and Section-6.4.1 
(Collection of samples for analysis) 
• Modified the safety assessments in the following sections: Synopsis (Safety 
Assessments) and Section-2.3 (Safety Variables) 
• Modified the Principal contacts information for reporting of Serious Adverse Events 
(SAEs) and in Section-8.5 (Serious Adverse Event Reporting) 
• Inserted a footnote in Study Design Schematic (Figure 1) 
• Modified Table 1 and Table 2 and Section-6.2.8 (Clinical Laboratory Tests) to reflect 
Table 1 and Table 2 modifications 
• Added a footnote in Table 3 
• Updated the Glossary of Abbreviations 
 
Page 9 of 145 
 


Protocol ZIN-130-1504  
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• Corrected the definition of severe neutropenia in Section-1.5.4 (Pharmacodynamic 
Endpoints) and 10.2.3 (Assessment of Pharmacodynamics and Pharmacokinetics) 
• Modified the Physical Examination in Section-6.2.4 
• Inserted the grading of laboratory abnormalities in the following sections: Synopsis 
(Safety analysis); Sections-6.2.8 (Clinical Laboratory Tests) and Section-10.2.5 
(Assessment of Safety) 
• Modified the Adverse Events of Special Interest Section-8.1.2 (Adverse Events of 
Special Interest) and Section-10.2.5.1 (Adverse Events) 
• Removed the preferred term tables Section-10.2.5.1 (Definitions of Adverse Events 
of Special Interest) 
• Updated the References Section-13.0 
• Updated the Appendix E Adverse events - categorized as SAEs to current version 
• Updated the Appendix F Neulasta® (pegfilgrastim, Amgen) Summary of Product 
Characteristics 
• Updated the Appendix H Neulasta® (pegfilgrastim, Amgen) Package Insert 
 
 
 
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Protocol ZIN-130-1504  
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PROTOCOL SYNOPSIS 
Sponsor: Hospira, Inc. (Hospira) 
Name of Finished Product: HSP-130 
Name of Active Ingredient: HSP-130 
Study Title: A Phase 1-2 ascending dose study to assess the pharmacodynamics, 
pharmacokinetics, and safety of HSP-130 in subjects with non-metastatic breast cancer 
following single-dose and multiple-dose administration by subcutaneous injection. 
Study Number: ZIN-130-1504 
OBJECTIVES 
Cycle 0: 
Primary Objective: 
• To characterize the pharmacodynamic (PD) response of absolute neutrophil count 
(ANC) and CD34+ count to HSP-130 at doses of 3 mg and 6 mg when administered as 
a single subcutaneous (SC) dose without chemotherapy to determine whether it is 
appropriate to study multiple doses of 3 mg with the context of background 
chemotherapy. 
Secondary Objective(s): 
• To characterize the pharmacokinetics (PK) of HSP-130 at doses of 3 mg and 6 mg 
when administered as a single SC injection without background chemotherapy. 
• To characterize the safety of HSP-130 at doses of 3 mg and 6 mg when administered as 
a single SC dose without background chemotherapy. 
Cycles 1-4: 
Primary Objective: 
• To characterize the PD response of duration of severe neutropenia (DSN) in Cycle 1 to 
HSP-130 over a range of doses when administered as single and multiple SC doses. 
Secondary Objective(s): 
• To characterize the PD response of ANC to HSP-130 in Cycles 1 and 4 over a range of 
doses when administered as single and multiple SC doses. 
• To characterize the PK of HSP-130 in Cycles 1 and 4 over a range of doses when 
 
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Protocol ZIN-130-1504  
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administered as single and multiple SC doses. 
• To characterize the safety of HSP-130 over a range of doses when administered as 
single and multiple SC doses. 
Study Design: An open-label, parallel group study characterizing the PD, PK, and safety 
of HSP-130 in subjects with non-distantly metastatic (non-Stage IV) breast cancer who 
have not previously received chemotherapy at any point prior to enrollment in this study 
(ZIN-130-1504). 
There are two aspects of the study. In the initial part of the study, 6 subjects will be 
sequentially enrolled to receive HSP-130 treatment (3 mg or 6 mg by SC injection) without 
concomitant or background chemotherapy. This treatment setting will, therefore be 
referred to as Cycle 0. Patients in Cycle 0 will receive HSP-130 during the period between 
biopsy and definitive surgery. 
The second group of subjects will receive up to 4 cycles of HSP-130, with concomitant 
background chemotherapy. Patients in Cycles 1-4 will receive HSP-130 after definitive 
surgery. Chemotherapy will consist of every 3 week taxane/cyclophosphamide-based 
regimen, i.e., docetaxel, doxorubicin and cyclophosphamide (TAC). 
Specifics of these two groups are addressed below.  Note that the 12 mg cohort will not be 
initiated until after discussion with the FDA as defined in Section 6.3.2. 
 
 
 
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Protocol ZIN-130-1504  
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Subjects in Cycle 0: 
Subject eligibility will be determined during a 14-day Screening Period.  Eligible subjects 
will be enrolled sequentially to each of the HSP-130 dose groups as follows: 
Regimen A: HSP-130, 3 mg, single SC injection in the deltoid region (n = 6) 
Regimen B: HSP-130, 6 mg, single SC injection in the deltoid region (n = 6) 
Initiation of Regimen B will be based on safety assessments in the first 5 evaluable 
subjects receiving Regimen A. This will include assessment of vital signs, concomitant 
medications, laboratory assessments including chemistry and hematology (complete blood 
count [CBC] and platelets), electrocardiogram (ECG), physical exam, and any adverse 
events (AEs) occurring post-dose administration through Day 30. The specific safety 
criteria for assessment for dose escalation are listed in Section 6.3.2 of the protocol. If, 
based on these assessments, there is no contraindication for dose escalation, screening for 
the subsequent dose level (Regimen B) can be initiated. 
In Cycle 0, Day 1 is the day that the subject receives HSP-130. Subjects obtain a baseline 
assessment of ANC and CD34+ count on Day 1 prior to receipt of HSP-130. Subjects will 
return for ANC, CD34+ measurement, and PK assessment for up to a maximum of 7 visits 
after HSP-130 dosing. 
After completion of Cycle 0, each of the subjects in these dosing groups will have 
completed their participation in assessment of HSP-130. The site will be offered 
reimbursement for treatment with EU-approved Neulasta in accordance with local standard 
of care by the Investigator with subsequent non-study chemotherapy regimen. 
Assessment of Regimen A (3 mg) for Cycles 1-4 will be conducted as follows: 
Based on the dose-response curve published by B. Yang and A. Kido (1), the average 
concentration (Cav) of pegfilgrastim (calculated from the time of pegfilgrastim 
administration to the time of ANC nadir) for the 6 mg dose was 72 ng/mL, which 
corresponds to 90% of maximum response (EC90). 
For a 3 mg dose, the estimated Cav was about 21 ng/mL, which corresponds approximately 
70% of maximum response (EC70). The expected response for a 3 mg dose (EC70) is 
77.8% of that from a 6 mg dose (EC90). 
It is expected that approximately 30% of subjects receiving 3 mg of pegfilgrastim would 
have a Cav value below the EC50 value. Because the dose of 3 mg of HSP-130 is 
potentially sub-therapeutic in breast cancer patients, this dose will be tested in Cycle 0 
without chemotherapy first. 
If the PD response (ANC and/or CD34+) of 3 mg HSP-130 and 6 mg HSP-130 in Cycle 0 
indicate that the 3 mg dose level is sub-therapeutic, the 3 mg dose level will not be 
included in Cycle 1-4 assessment. This design feature will ensure that no subject with 
 
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Protocol ZIN-130-1504  
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chemotherapy will be treated with sub-therapeutic dose of HSP-130. 
If, however, the individual PD measurement (ANC and/or CD34+) of the treatment with 
HSP-130 3 mg and 6 mg in Cycle 0 are commensurate, as defined above, then treatment 
with Regimen A with background chemotherapy will be initiated. 
Subjects in Cycles 1-4: 
When enrollment of the 6 subjects receiving Regimen B in Cycle 0 is completed, an 
additional 12 subjects will be enrolled on Regimen B and entered in Cycle 1-4 as defined 
below. Patients in Cycles 1-4 will receive HSP-130 after definitive surgery. Eligible subjects 
will be enrolled sequentially to each of the HSP-130 dose groups as follows: 
Regimen B: HSP-130, 6 mg, single SC injection in the deltoid region, at least 24 hours 
after administration of chemotherapy in Cycle 1, Cycle 2, Cycle 3, and Cycle 4 
(n = 12). 
Potential Regimen A (3 mg) with background chemotherapy: Inclusion of this 
cohort will be based on assessment of comparability between Regimens A and B in 
Cycle 0 for ANC and CD34+ as defined above. If performed, this regimen will be 
HSP-130, 3 mg, single SC injection in the deltoid region, at least 24 hours after 
administration of chemotherapy in Cycle 1, Cycle 2, Cycle 3, and Cycle 4 (n = 12), as 
appropriate. 
While noted in the protocol schema which is included as Figure 1, the 12 mg cohort will 
not be initiated until Hospira has analyzed the data from the Cycle 0 for 3 mg and 6 mg 
cohorts and the Cycles 1-4 for 6 mg cohort (and 3 mg cohort, if performed) and reviewed 
the results with the FDA. Escalation to 12 mg will only proceed if the exposure pattern of 
the PK/PD responses suggests that higher doses are required. Please see section 6.3.2 for 
additional details. 
During Cycles 1-4 for each of the regimens, subjects will receive treatment with HSP-130 
at 24 hours after administration of chemotherapy (Day 2). Subjects will return for ANC 
measurement and PK assessment for up to an additional 7 visits after dosing. 
Subjects will return for a Follow-up Visit 30 (±2) days after the dose of HSP-130 in 
Cycle 4. 
Number of Centers: Approximately 10 sites in Europe. 
Study Population: 
A total of 24-36 patients will be enrolled initially; a further 12 patients totaling 
approximately 36-48 patients will be treated if the 12 mg cohort is enrolled, as defined in 
Section 6.3.2. 
• The number of 24 patients includes 12 patients in Cycle 0 and 12 patients in the 
 
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Protocol ZIN-130-1504  
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Cycles 1-4 6 mg cohort. 
• The number of 36 patients includes the additional 12 patients if the second 3 mg cohort 
is included in the Cycles 1-4 part of the study. 
• The number of 48 patients includes the potential for 12 patients in the 12 mg cohort if, 
after review of the data in the up to 36 patients with the FDA, a decision is jointly 
made based on the exposure pattern of the PK/PD responses that higher doses are 
required. 
Approximately 12 subjects will be enrolled into two cohorts to receive ascending doses of 
HSP-130 (6 subjects on Regimen A [3 mg] and 6 subjects on Regimen B [6 mg] without 
background chemotherapy. 
Twelve subjects will be enrolled in the 6 mg cohort in the setting of background 
chemotherapy. As mentioned, enrollment in a 12 mg cohort will not be initiated until 
criteria addressed in section 6.3.2 are met. 
An additional 12 subjects will be enrolled into Regimen A (3 mg) as defined by the 
protocol in Section 1.5.1. 
It is recommended that rescue management for subjects who develop febrile neutropenia 
(FN) during the study be consistent with several recent publications (2), (3), (4) and recent 
Cochrane review (5). Management of FN should also include consideration of 
locale-driven susceptibility patterns. 
Key Inclusion Criteria for all study subjects (See Section 4.2 for full Inclusion Criteria) 
A subject will be eligible for study participation if all of the following criteria are met at 
Screening: 
1. Is informed, has been given ample time and opportunity to read about participation in 
the study and has signed and dated the written informed consent form approved by an 
Independent Ethics Committee (IEC) prior to any study related activities 
2. Females ≥ 18 years 
3. Histologically confirmed and documented invasive breast cancer 
4.  Breast cancer without evidence of distant metastases (non-Stage IV) based on staging 
work-up  
5. Chemotherapy naïve, who have not received chemotherapy in the neoadjuvant setting 
and who are candidates for chemotherapy in the adjuvant setting of 
taxane/cyclophosphamide-based regimen, i.e., TAC as background chemotherapy 
6. Zubrod/WHO/ECOG performance status ≤ 2 
 
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Protocol ZIN-130-1504  
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7. Adequate bone marrow, hepatic, and renal function reserve as evidenced by: 
a. Hemoglobin ≥ 10 mg/dL 
b. ANC ≥ 1.5 x 109/L 
c. Platelet count of ≥ 100 x 109/L 
d. Total bilirubin ≤ 2 mg/dL 
e. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 
≤ 3 x the upper limit of normal (ULN) of the reference lab 
f. Serum creatinine of ≤ 1.5 x ULN for reference lab or estimated glomerular 
filtration rate (eGFR) of ≥ 60 mg/min 
8. Subjects of childbearing potential, and their partners, agree to pregnancy prevention 
throughout the duration of the study (through the Follow-up Visit). Specific type of 
pregnancy prevention should be discussed with, and acceptable to, the treating 
oncologist in the context of the tumoral hormone receptor status and is summarized in 
Section 4.2 
9. Able to understand verbal or written instructions and comply with all study 
requirements, to communicate effectively with study personnel and is available for the 
planned duration of the study 
Key Exclusion Criteria (See Section 4.3 for full Exclusion Criteria) 
A subject will NOT be eligible for study participation if any of the following criteria are 
met at Screening: 
1. Previous granulocyte colony-stimulating factor (G-CSF) exposure, including 
filgrastim, lenograstim, pegfilgrastim, lipegfilgrastim, granulocyte/macrophage colony 
stimulating growth factor (GM-CSF), or any other branded or biosimilar G-CSF 
2. Prior autologous stem cell harvest of any type 
3. Drug sensitivity, allergic reaction, or known hypersensitivity or idiosyncratic reaction 
to Escherichia coli (E. coli)-derived proteins, filgrastim, other G-CSFs, or pegylated 
agents 
4. Known hypersensitivity to docetaxel, polysorbate 80, or doxorubicin 
5. Chemotherapy other than that included in this study (i.e., 
taxane/cyclophosphamide-based regimen, i.e., TAC) or neoadjuvant chemotherapy; or 
known immunosuppressive agents including chronic oral corticosteroid use, or 
radiation therapy within 4 weeks of first dose of HSP-130, prior bone marrow or stem 
 
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Protocol ZIN-130-1504  
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cell transplantation, or malignancy within 5 years 
6. Known HER2+ (overexpressing breast cancer) 
7. Known triple negative (estrogen receptor-negative, progesterone receptor-negative and 
HER2-negative) breast cancer 
8. Medical conditions including but not limited to: Known sickle cell disease, known 
severe persistent drug-induced myelosuppression; severe uncontrolled cardiac disease 
as defined in Section 4.3; any malignancy other than breast with the exception of 
adequately treated squamous or basal cell carcinoma or the skin or cervical carcinoma 
in situ within 5 years; pregnancy or lactation; received live, live-attenuated, or non-live 
vaccine within 4 weeks 
9. Current or recent treatment (within 30 days before the first administration of the 
HSP-130) with any other Investigational Medicinal Product 
10. Patient has evidence of any other coexisting disease or medical or psychological 
condition, metabolic dysfunction, physical examination finding or clinical lab finding 
giving reasonable suspicion of a disease or condition that contraindicated the use of an 
HSP-130, or patient is high risk for treatment complication 
Investigational medicinal products, dosage and route of administration: 
Test product: HSP-130, 3 mg, 6 mg or 12 mg administered as a SC injection  
(Note: 12 mg will be administered as 2 concurrent injections and only if the decision is 
made with the FDA to pursue a 12 mg dose.  See Section 6.3.2 for details.) 
In Cycle 0, subjects will receive treatment with HSP-130 only, without concomitant 
background chemotherapy.  
In Cycles 1-4, subjects will receive treatment with HSP-130 concomitantly with 
chemotherapy. 
Duration of Treatment: 
Subjects on Regimen A or Regimen B during Cycle 0 will receive a single dose of 
HSP-130 (3 mg or 6 mg) and be in the study for approximately 30 (±2) days and will not 
receive concomitant background chemotherapy. 
Subjects receiving Regimen B (6 mg), and, if performed, multiple dose Regimen A (3 mg) 
[and Regimen C (12 mg) if the decision is made with the FDA to pursue a 12 mg dose. See 
Section 6.3.2 for details], will receive up to 4 doses of HSP-130 in the context of 4 cycles 
of chemotherapy (≥ 21 days per cycle). Exclusive of chemotherapy-related treatment 
delays, these subjects will participate in the study, for approximately 94 days (including 
Follow-up Visit). 
 
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Protocol ZIN-130-1504  
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Pharmacodynamics and Pharmacokinetics of HSP-130 
Cycle 0: 
Pharmacodynamic Sampling/Collection: 
Blood samples for ANC (2.7 mL) and CD34+ count (2.0 mL) will be collected by 
venipuncture into evacuated collection tubes within 1 hour prior to dose administration on 
Day 1 and at 48, 96, 144, 192, 240, and 312 hours post-dose. 
Pharmacokinetic Sampling/Collection: 
Blood samples (7.0 mL) for HSP-130 assay will be collected by venipuncture into 
evacuated collection tubes within 1 hour prior to dose administration on Day 1 and at 6, 
12, 24, 48, 96, 144, 192, 240, and 312 hours post-dose. 
Pharmacodynamic and Pharmacokinetic Assessments: 
Pharmacodynamic Variables: 
Primary Variable: Area under the effect curve for ANC (AUECANC) 
Secondary Variables: Maximum effect for ANC (ANC_Emax), time of maximum effect 
for ANC (ANC Tmax), Area under the effect curve for CD34+ (AUECCD34+), maximum 
effect for CD34+ count (CD34+_Emax), time of maximum effect for CD34+ count  
(CD34+ Tmax) 
The PD variables will be calculated using non-compartmental methods. 
Pharmacokinetic Variables: 
Primary Variables: Area under the serum HSP-130 versus time curve from the time of 
dose administration to time infinity (AUC0-∞) and the maximum observed serum HSP-130 
concentration (Cmax) 
Secondary Variables: Area under the serum HSP-130 versus time curve from the time of 
dose administration to the time of last measurable concentration (AUC0-t), the time of 
maximum serum HSP-130 concentration (Tmax), elimination half-life (t1/2), elimination 
rate constant (λz), and apparent clearance (CL) 
The PK variables will be calculated using non-compartmental methods. 
Cycles 1-4:  
Pharmacodynamic Sampling/Collection: 
Blood samples for ANC (2.7 mL) will be collected by venipuncture into evacuated 
collection tubes within 1 hour prior to dose administration on Day 2 of the chemotherapy 
 
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Protocol ZIN-130-1504  
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cycle and at 48, 96, 144, 192, 240, and 312 hours post-dose. This sample collection 
schedule will be applied to Cycles 1 and 4 with HSP-130 treatment groups. 
Pharmacokinetic Sampling/Collection: 
Blood samples (7.0 mL) for HSP-130 assay will be collected by venipuncture into 
evacuated collection tubes within 1 hour prior to dose administration on Day 2 of the 
chemotherapy cycle and at 6, 12, 24, 48, 96, 144, 192, 240, and 312 hours post-dose. This 
sample collection schedule will be applied to Cycles 1 and 4 with HSP-130 treatment 
groups. 
Pharmacodynamic and Pharmacokinetic Assessments: 
Pharmacodynamic Variables: 
Primary Variable: Duration of severe neutropenia (DSN). DSN is defined as days with 
grade 4 neutropenia (ANC < 0.5 x 109/L) in Cycle 1. 
Secondary Variables: Duration of severe neutropenia (DSN) in Cycle 4. ANC nadir 
concentration, time of nadir concentration, area under the effect curve (AUEC), incidence 
of FN, defined as tympanic or axillary body temperature > 38.5°C for > 1 hour with 
ANC < 1.0 x 109/L, incidence of severe neutropenia (grade 4, ANC < 0.5 x 109/L) and time 
to ANC recovery (the first day with ANC ≥ 2.0 x 109/L after any day with 
ANC < 2.0 x 109/L) in Cycle 1 and Cycle 4. 
The PD variables will be calculated using non-compartmental methods. 
Pharmacokinetic Variables: 
Primary Variables: AUC0-t and Cmax 
Secondary Variables: AUC0-∞, Tmax, t1/2, λz, and CL 
The PK variables will be calculated using non-compartmental methods. 
Safety Assessments: 
The safety variables to be assessed include adverse events, including Adverse Events of 
Special Interest, laboratory assessments and ECG at Follow-up Visit at study end and as 
clinically indicated, vital signs, and physical examination. These will be performed on 
patients receiving HSP-130 without (Cycle 0) or with chemotherapy (Cycles 1-4).  
Cycle 0: 
Safety assessment includes assessment of vital signs, concomitant medications, laboratory 
assessments including chemistry and hematology (CBC and platelets), ECG, physical 
exam, and any AEs occurring post-dose administration through Day 30. After completion 
of Cycle 0, each of the subjects in these dosing groups will have completed their 
 
Page 19 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
participation in assessment of HSP-130. The site will be offered reimbursement for 
treatment with EU-approved Neulasta in accordance with local standard of care by the 
Investigator with subsequent non-study chemotherapy regimen. 
Cycles 1-4: 
To begin full-dose chemotherapy on Day 1 of the next cycle (≥ Day 21 of the previous 
cycle), ANC must have recovered to ≥ 1.5 x 109/L and platelet counts to ≥ 100 x 109/L. If 
these requirements are not met, postponement of the following cycle for up to 2 weeks will 
be acceptable. Both ANC and platelets will be determined on Day 15 and Day 20 of each 
cycle by a central laboratory so that results are available at the beginning of the next cycle. 
In subjects who experience FN and/or ANC < 0.5 x 109/L for > 1 week, severe or 
cumulative cutaneous reactions, or severe (grade 3 or 4) peripheral neuropathy during 
therapy, the chemotherapy timing and dose will be modified as deemed appropriate by 
treating physician. Changes in patients TAC chemotherapy regimen will be determined by 
the patients treating physician in the context of known TAC toxicity profile and 
management. Subjects who withdraw prior Cycle 2 may be replaced to support the full 
complement subjects (minimum of 8 evaluable subjects) for primary endpoint data 
generation for Cycle 1. 
Anti- antibody assessments: 
Cycle 0: 
Blood samples (7.0 mL) for anti-HSP-130 antibodies assessment will be collected on 
Day 1 (prior to dose), on Day 14 and Day 20. 
Cycles 1-4: 
Blood samples (7.0 mL) for anti-HSP-130 antibodies assessment will be collected on 
Day 2 (prior to study drug dose) and on Day 20 in Cycles 1 and 4. 
Statistical Methods: 
Analysis Populations: 
Safety Population: All subjects who receive at least one dose of HSP-130 will be included 
in the Safety Population. All safety analyses will be conducted on the Safety Population. 
Full analysis set (FAS): All subjects who receive at least one dose of HSP-130 in the 
context of concomitant chemotherapy will be included in the FAS.  In analysis of a 
particular parameter for a particular cycle(s), only those subjects who have sufficient data 
in the cycle(s) to calculate the parameter will be included. Sufficient data is defined as 
having more than 3 measurable values where the parameter can be reliably calculated. 
Subjects who have confirmed positive anti-HSP-130 antibody results will not be included. 
 
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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Sample Size Estimation: 
No formal sample size calculation was conducted. 
Pharmacodynamic analysis: 
Descriptive statistics including number of observations (N), mean, standard deviation (SD) 
and associated coefficient of variation (CV), minimum and maximum for each PD 
parameter by treatment will be reported. 
If the PD response (AUECANC and/or AUECCD34+) of 3 mg HSP-130 and 6 mg HSP-130 in 
Cycle 0 indicate that the 3 mg dose level is sub-therapeutic, the 3 mg dose level will not be 
included in Cycle 1-4 assessment. This design feature will ensure that no patient with 
chemotherapy will be treated with sub-therapeutic dose of HSP-130. 
The primary PD parameters of AUECANC results from Cycle 0 and DSN results from 
Cycle 1 will be assessed to determine appropriate doses for Phase 3 studies. Additional PD 
results may be assessed as appropriate. 
Pharmacokinetic analysis: 
Descriptive statistics including N, mean, SD, minimum and maximum for each PK 
parameter by treatment will be reported. 
Safety analysis: 
Treatment emergent adverse events will be summarized by system organ class and 
preferred terms. Descriptive statistics including N, mean, SD, minimum and maximum for 
numerical data, and counts and frequency for categorical data, will be tabulated for 
laboratory tests, and vital signs by treatment group. Grading of laboratory abnormalities 
will be according to the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03 (6). 
 
 
 
Page 21 of 145 
 


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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Figure 1  
Study Design Schematic 
 
Note that the 12 mg cohort will not be initiated until after discussion with the FDA as defined in Section 6.3.2 
28-44 days are guideline time period based on site scheduling and procedures. 
. 
 
 
Page 23 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
 
Table 1. 
Schedule of Study Activities: Cycle 0: 3 mg or 6 mg SC Injection (s) Without Background 
Chemotherapy 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visit  
30 (± 2) 
Study Day 
-14 to -1 
1 
2 
3 
5 
7 
9 
11 
14 
20 
Clinical Assessments/Activities 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
X 
Body Weight & Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CISNE b  
 
X 
 
 
 
X 
 
 
 
X 
X 
FACT-N c 
 
X 
 
 
 
 
 
 
 
X 
X 
Pregnancy Test d 
X 
 
 
 
 
 
 
 
 
 
X 
HSP-130 Administration 
 
X 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
X 
Chest X-ray (if none within 1 month) 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments e 
 
Page 24 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Table 1. 
Schedule of Study Activities: Cycle 0: 3 mg or 6 mg SC Injection (s) Without Background 
Chemotherapy 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visit  
30 (± 2) 
Study Day 
-14 to -1 
1 
2 
3 
5 
7 
9 
11 
14 
20 
Clinical Chemistry 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Hematology (including complete blood count + 
Platelets) 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Serology (anti-HIV Abs) 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
X 
Spot urine for protein/creatinine ratio (PCR) 
X 
 
 
X 
 
 
 
X 
 
X 
X 
Pharmacodynamic Sampling f  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Pharmacokinetic Sampling g  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Anti-HSP-130 antibody Sampling h 
 
X 
 
 
 
 
 
 
X 
X 
 
a. Vital Signs will be measured pre-dose, at approximately the same time at Day 1, each day of PK/PD sampling (Day 2-Day 14), Day 20 and at Follow-up 
Visit 
b. Clinical Index of Stable Febrile Neutropenia (CISNE) : assessment will be completed for each episode of febrile neutropenia 
c. As available in local language 
d. Serum pregnancy test for all subjects except those who are postmenopausal for 5 years or have undergone surgical sterilization 
e. The total blood volume for all laboratory assessments is approximately 100 mL 
f. Pharmacodynamic sampling for absolute neutrophil count (ANC), CD34+ count will be collected within 1 hour prior to dose administration and at 48, 96, 
144, 192, 240, and 312 hours post-dose 
g. Pharmacokinetic sampling will be collected within 1 hour prior to dose at Day 1, and at 6, 12, 24, 48, 96, 144, 192, 240, and 312 hours post-dose 
h. Anti-HSP-130 antibody sampling will be collected pre-dose on Day 1 as well as on Day 14 and Day 20. 
 
 
 
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Protocol ZIN-130-1504  
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Table 2. 
Schedule of Study Activities: Cycles 1 and 4 for Subjects Receiving 6 mg or 12 mg¥ SC Injection(s) 
24 hours Post-Chemotherapy Administration Each Cycle* 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visiti 
(Cycle 4) 
Study Day 
-14 to -1 
1 
2 
3 
4 
6 
8 
10 
11 
12 
15 
20 
30 (± 2) 
Clinical Assessments/Activities 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs a 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
WHO Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CISNE b 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
FACT-N c 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Test d 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HSP-130 
Administration e 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
12-lead 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Chest X-Ray (if none 
within 1 month) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2. 
Schedule of Study Activities: Cycles 1 and 4 for Subjects Receiving 6 mg or 12 mg¥ SC Injection(s) 
24 hours Post-Chemotherapy Administration Each Cycle* 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visiti 
(Cycle 4) 
Study Day 
-14 to -1 
1 
2 
3 
4 
6 
8 
10 
11 
12 
15 
20 
30 (± 2) 
Chemotherapy  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments f 
Clinical Chemistry 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
Hematology (including 
complete blood count + 
platelets) 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Serology (anti-HIV 
Abs) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Spot urine for 
protein/creatinine ratio 
(PCR) 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Pharmacodynamic 
Sampling g  
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Pharmacokinetic 
Sampling h  
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Anti-HSP-130 antibody 
Sampling i 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
¥ Enrollment in the 12 mg cohort will occur only after 
• review with the FDA of data from Cycle 0 cohorts, and the Cycles 1-4 for 6 mg cohort (and 3 mg cohort, if performed) and 
• only if the exposure pattern of the PK/PD response suggest that higher doses are required.  Additional details are available regarding the 12 mg cohort 
and associated stopping rules in section 6.3.2. 
*If decision is made to carry out Regimen A in Cycles 1 and 4, subjects will follow same activities listed above 
a. Vital Signs will be measured pre-dose, at approximately the same time at Day 2, and each day of PK/PD sampling (Day 3-Day 15), Day 18, Day 20, and at 
Follow-up Visit 
 
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b. Clinical Index of Stable Febrile Neutropenia (CISNE): assessment will be completed for each episode of febrile neutropenia 
c. As available in local language 
d. Serum pregnancy test for all subjects except those who are postmenopausal for 5 years or have undergone surgical sterilization 
e.  In Cycles 1 and 4, subjects will receive treatment with HSP-130 on Day 2 (no less than 24 hours after administration of chemotherapy) 
f. The total blood volume for all laboratory assessments is approximately 250 mL 
g. Pharmacodynamic sampling for absolute neutrophil count (ANC) will be collected within 1 hour prior to dose administration and at 48, 96, 144, 192, 240, 
and 312 hours post-dose 
h. Pharmacokinetic sampling will be collected within 1 hour prior to dose and at 6, 12, 24, 48, 96, 144, 192, 240, and 312 hours post-dose 
i. 
Anti-HSP-130 antibody sampling will be collected pre-dose on Day 2 and on Day 20 
j. 
These assessments will be carried out at the end of Cycle 4 or at the time of subject termination during the planned course of the study 
 
 
 
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Table 3. 
Schedule of Study Activities: Cycles 2 and 3 for Subjects Receiving 6 mg or 12 mg¥ SC injection(s) 
24 hours Post-Chemotherapy Administration Each Cycle* 
Evaluation 
Site Visit 
Study Day 
1 
2 
3 
6 
10 
11 
12 
15 
20 
Clinical Assessments/Activities 
Clinical Chemistry a 
 
 
X 
X 
X 
X 
X 
 
X 
Hematology (including 
complete blood count + 
platelets) a 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
X 
 
 
 
X 
X 
WHO Performance Status 
X 
X 
 
X 
 
 
 
X 
X 
CISNE b 
 
X 
 
 
 
 
 
 
 
FACT-N c 
 
X 
 
 
 
 
 
 
 
HSP-130 Administration** 
 
X 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
 
X 
 
 
 
X 
X 
Concomitant Medications 
X 
X 
 
X 
 
 
 
X 
X 
Chemotherapy  
X 
 
 
 
 
 
 
 
 
¥ Enrollment in the 12 mg cohort will occur only after 
• review with the FDA of data from Cycle 0 cohorts, and the Cycles 1-4 for 6 mg cohort (and 3 mg cohort, if performed) and 
• only if the exposure pattern of the PK/PD response suggest that higher doses are required.  Additional details are available regarding the 12 mg cohort 
and associated stopping rules in section 6.3.2. 
*If decision is made to carry out Regimen A in Cycles 2 and 3, subjects will follow the same activities listed above 
** In Cycles 2-3, subjects will receive treatment with HSP-130 on Day 2 (no less than 24 hours after administration of chemotherapy).  Dose levels to be 
administered in Cycle 1-4 will be determined from the results of Cycle 0.  This determination will be based on the following considerations: 
1. Evidence of effect of Regimen A (HSP-130 3 mg, single SC injection) on ANC and CD34+ counts in Cycle 0 is commensurate as defined by the 
protocol with that observed for Regimen B (HSP-130, 6 mg, single SC injection). If data for subjects receiving Regimen A in Cycle 0 demonstrate lack 
 
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of effect or significantly diminished effect, Regimen A will not be brought forward to be studied further. Lack of effect of the lowest dose of HSP-130 
studied in subjects not receiving a myelosuppressive chemotherapy regimen will preclude use in subjects receiving myelosuppressive chemotherapy 
(taxane/cyclophosphamide-based regimen, i.e., TAC). 
2. Lack of safety concerns as defined by the Medical Monitor based on the specific safety considerations for any of the dose regimens. 
a. On Days 3, 10, 11, and 12, blood samples will be collected for Clinical Chemistry and Hematology and does not necessitate a site visit. 
b. Clinical Index of Stable Febrile Neutropenia (CISNE): assessment will be completed for each episode of febrile neutropenia 
c. As available in local language 
 
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GLOSSARY OF ABBREVIATIONS  
Abbreviation/Acronym 
Definition 
AEs 
adverse events 
ANC 
absolute neutrophil count 
ANC_Emax 
maximum effect for ANC 
ANC_Tmax 
time of maximum effect for ANC 
ARDS 
acute respiratory distress syndrome 
AUC0-∞ 
area under the serum HSP-130 versus time curve from the time 
of dose administration to time infinity 
AUC0-t 
area under the serum HSP-130 versus time curve from the time 
of dose administration to time of last measurable concentration 
AUEC 
area under the effect curve 
AUECANC 
area under the effect curve for ANC 
AUECCD34+ 
area under the effect curve for CD34+  
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CD34+_Emax 
maximum effect for CD34+ count 
CD34+_Tmax 
time of maximum effect for CD34+ count 
CFR 
U.S. Code of Federal Regulations 
CIN 
chemotherapy-induced neutropenia 
CISNE 
clinical index for stable febrile neutropenia 
CL 
apparent clearance 
Cmax 
maximum observed serum HSP-130 concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DSN 
duration of severe neutropenia 
E. Coli 
Escherichia coli 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
 
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Abbreviation/Acronym 
Definition 
EDC 
electronic data capture 
FACT-N 
Functional Assessment of Cancer Therapy - Neutropenia 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FN 
febrile neutropenia 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
HIVAb 
human immunodeficiency virus antibody 
HRQOL 
health-related quality of life 
HSP-130 
Hospira Pegylated Recombinant Human Methionyl G-CSF or 
Hospira pegylated filgrastim 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICH GCP 
International Conference on Harmonisation Tripartite Guideline 
on Good Clinical Practice 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
kD 
kilodaltons 
MASCC 
Multinational Association for Supportive Care in Cancer 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mg 
milligram 
mL 
milliliter 
mPEG 
monomethoxypolyethylene glycol 
N 
number of observations 
NAb 
neutralizing antibody 
PCR 
protein/creatinine ratio 
PD 
pharmacodynamics 
PFS 
pre-filled syringes 
PK 
pharmacokinetics 
PS 
performance status 
PT 
preferred term 
 
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Abbreviation/Acronym 
Definition 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SPC 
Summary of Product Characteristics  
SMQ 
standard MedDRA queries 
SOP 
standard operating procedure 
TAC 
docetaxel, doxorubicin, and cyclophosphamide 
t1/2 
elimination half-life 
TEAEs 
treatment-emergent adverse events 
Tmax 
time to maximum serum HSP-130 concentration 
ULN 
upper limit of normal 
USPI 
United States Package Insert  
WBC 
white blood cells 
WHO 
World Health Organization 
WHO PS 
World Health Organization Performance Status (also known as 
ECOG PS or Eastern Cooperative Oncology Group PS or 
Zubrod PS) 
WMA 
World Medical Association 
λz 
elimination rate constant  
 
 
 
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1 
BACKGROUND AND RATIONALE 
1.1 
Background to the Disease 
Neutropenia is a laboratory diagnosis and is defined as the reduction in the absolute number 
of neutrophils in the peripheral blood or circulation. Neutrophils are mature phagocytic 
leukocytes of the granulocyte series; are formed by bone marrow and released into 
circulation; are the predominant component of circulating white cells, and are the 
predominant leukocyte involved in inflammation. Circulating neutrophils actually represent 
only approximately 3% of the body’s total neutrophil numbers, with the vast majority in the 
bone marrow reserve pool and the remainder in the tissue and marginated pool attached to 
vascular endothelial cells (7),(8). 
Neutropenia is generally characterized as mild, moderate, or severe based on the circulating 
absolute neutrophil count (ANC) (7), (9), (10). 
• Mild neutropenia: ANC 1.0-1.5 × 109/L 
• Moderate neutropenia: ANC 0.5-1.0 × 109/L 
• Severe neutropenia: ANC < 0.5 × 109/L 
In general, only subjects with severe neutropenia have been found to be at risk for major 
pyogenic infections and life-threatening infections, regardless of the underlying etiology of 
the neutropenia, congenital or acquired (11). 
Myelosuppressive chemotherapy is an important iatrogenic cause of neutropenia. While 
within a given individual, many chemotherapeutic agents can be associated with neutropenia, 
there are a number of agents that are consistently associated with elevated risk for its 
development. These are listed in Table 4 and are consistent with the medical literature as well 
as national and international guidelines for management of chemotherapy-induced 
neutropenia (CIN) (9). 
Low ANC increases the risk of fevers (febrile neutropenia) and life-threatening infections 
(12), (13). Febrile neutropenia is defined by the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03, categorized as Grades 3 to 5 as follows (6): 
• Grade 3: ANC < 1000/mm3 and a single temperature of > 38.3°C (101°F) or a 
sustained temperature of ≥ 38°C (100.4°F) for > 1 hour  
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death 
 
 
 
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Table 4. 
Factors to Consider in Assessing Risk of a Febrile Neutropenic 
Episode in Patients Undergoing Cytotoxic Chemotherapy for 
Malignancy 
Factor 
Effect on Risk 
Reported 
FN Rate 
(%) 
95% CI 
(%) 
Patient Characteristics 
 
 
 
Advanced age 
Risk increases if age ≥ 65 years 
-- 
-- 
ECOG PS 
Risk increases if PS ≥ 2 
-- 
-- 
Nutritional status 
Risk increases if albumin < 35 g/L 
-- 
-- 
Prior FN episode 
Risk in cycles 2-6 is 4x greater if 
FNE occurs in cycle 1 
-- 
-- 
Comorbidities 
FN odds increase by 27%, 67%, and 
125%, respectively, for 1, 2, or ≥ 3 
comorbidities 
-- 
-- 
Underlying malignancy 
-- 
-- 
-- 
Cancer diagnosis a 
-- 
-- 
-- 
Acute leukemia/MDS 
-- 
85 to 95 
-- 
Soft tissue sarcoma 
-- 
27 
19 to 34.5 
NHL/myeloma 
-- 
26 
22 to 29 
Germ cell carcinoma 
-- 
23 
16.6 to 29 
Hodgkin lymphoma 
-- 
15 
6.6 to 24 
Ovarian carcinoma 
-- 
12 
6.6 to 
17.7 
Lung cancers 
-- 
10 
9.8 to 
10.7 
Colorectal cancers 
-- 
5.5 
5.1 to 5.8 
Head and neck 
carcinoma 
-- 
4.6 
1.0 to 8.2 
Breast cancer 
-- 
4.4 
4.1 to 4.7 
Prostate cancer 
-- 
1 
0.9 to 1.1 
Cancer stage 
Risk increases for advanced stage 
(≥ 2) 
-- 
-- 
Remission status 
Risk increases if not in remission 
-- 
-- 
Treatment response 
Risk is lowest if patient has a CR 
If patient has a PR, FN risk is 
greater for acute leukemia than for 
solid tissue malignancies 
FN risk is higher if persistent, 
refractory, or progressive disease 
despite treatment 
-- 
-- 
Treatment for 
malignancy 
 
-- 
-- 
 
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Table 4. 
Factors to Consider in Assessing Risk of a Febrile Neutropenic 
Episode in Patients Undergoing Cytotoxic Chemotherapy for 
Malignancy 
Factor 
Effect on Risk 
Reported 
FN Rate 
(%) 
95% CI 
(%) 
Cytotoxic regimen 
Risk is higher with regimens that 
administer: 
-- 
-- 
 
Anthracyclines at doses ≥ 90 mg/m2 
-- 
-- 
 
Cisplatin at doses ≥ 100 mg/m2 
-- 
-- 
 
Ifosfamide at doses ≥ 9 g/m2 
-- 
-- 
 
Cyclophosphamide at doses 
≥ 1 g/m2 
-- 
-- 
 
Etoposide at doses ≥ 500 mg/m2 
-- 
-- 
 
Cytarabine at doses ≥ 1 g/m2 
-- 
-- 
 
High dose-density (e.g., CHOP-14) 
-- 
-- 
 
Anthracycline + taxane + 
cyclophosphamide, or anthracycline 
+ gemcitabine for breast cancer 
-- 
-- 
Dose-intensity 
Increased risk if > 85% of 
scheduled doses are administered b 
-- 
-- 
Degree and duration of 
GI and/or oral mucositis 
Risk is increased if NCI mucositis 
grade ≥ 3 (GI) or if peak OMAS 
score ≥ 2 
-- 
-- 
Degree and duration of: 
 
-- 
-- 
Neutropenia 
ANC < 500/µL ≥ 7 days 
-- 
-- 
Lymphopenia 
ALC < 700/µL (ANC surrogate) 
-- 
-- 
Monocytopenia 
AMC < 150/µL (ANC surrogate) 
-- 
-- 
Prophylactic use of 
WBC growth factors 
Reduced risk for patients selected as 
in ASCO guideline 
-- 
-- 
a Highest to lowest risk 
b Note that the Panel recommends against routine decreases in dose-intensity as a means of preventing FN 
ALC: absolute lymphocyte count; AMC: absolute monocyte count; ANC: absolute neutrophil count; ASCO: 
American Society of Clinical Oncology; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; 
CR: complete response; ECOG: Eastern Cooperative Oncology Group; FN: fever and neutropenia; FNE: febrile 
neutropenic episode; GI: gastro intestinal; MDS: myelodysplastic syndrome; NCI: National Cancer Institute; 
NHL: non-Hodgkin lymphoma; OMAS: Oral Mucositis Assessment Scale; PR: partial response;  
PS: performance status; WBC: white blood cells. 
Source: Reference (9). 
Implications of CIN and febrile neutropenia are manifold and include infection and 
overwhelming sepsis and its associated complications, including death, increased risk for 
hospitalization as well as compromised oncologic outcomes including treatment delays, 
reduction in chemotherapeutic dose, or both. Neutropenia is a common dose-limiting adverse 
effect. As a result, patients can receive suboptimal cancer therapy leading to compromised 
 
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outcomes, including increased morbidity and mortality and decreased survival (11), (12), 
(13), (14), (15), (16). International guidelines for prevention and management of CIN include 
the consistent recommendation of use of supportive care with myeloid growth factors in 
patients undergoing myelosuppressive chemotherapy with a specified threshold of risk, 
generally of risk for at least 20% of patients receiving the myelosuppressive agent or regimen 
(7), (16), (17). 
Endogenous granulocyte-colony stimulating factor (G-CSF) is the primary regulating factor 
for neutrophils (18). The G-CSF acts by binding to G-CSF receptors located on the cell 
surface of the whole neutrophil lineage, resulting in stimulated proliferation, differentiation, 
commitment, and end cell functional activation. Endogenous G-CSF is known to stimulate 
proliferation of the mitotic cells, to reduce the maturation time of the non-mitotic cells in the 
bone marrow and to prolong the life-span and enhance the function of mature neutrophils. 
Endogenous G-CSF is produced by different cell types including macrophages, monocytes, 
fibroblasts, stromal cells in bone marrow, and endothelial cells (7). Endogenous G-CSF is 
triggered by inflammatory agents as well as by lipopolysaccharide released from bacteria. 
Recombinant human G-CSFs can vary slightly based on whether it is produced in 
Escherichia coli (E. coli) [filgrastim] or Chinese hamster ovary (CHO) cells [lenograstim]. 
The former is identical to the natural sequence predicted from human DNA sequence 
analysis‚ except for the addition of an N-terminal methionine necessary for expression in 
E. coli. Filgrastim is a water soluble 175 amino acid protein with a molecular weight of 
approximately 19 kilodaltons (kD) and is obtained from the bacterial fermentation of a strain 
of E. coli transformed with a genetically engineered plasmid containing the human G-CSF 
gene. Also based on production in E. coli‚ filgrastim is non-glycosylated, in contrast to 
endogenous G-CSF, which is glycosylated (19). 
Filgrastim has been shown to enhance neutrophil production and to mobilize hematopoietic 
stem cells from bone marrow to the blood in human subjects (19). Based on its circulating 
half-life, filgrastim must be given daily to prevent or treat CIN. 
Protein pegylation is widely utilized to prolong the circulating half-life of biologic agents. 
Hospira has developed a pegylated G-CSF, referred to as HSP-130 (Hospira Pegylated 
Recombinant Human Granulocyte Colony-Stimulating Factor). The proposed pegylated 
recombinant human G-CSF is a covalent conjugate of recombinant methionyl G-CSF and a 
20 kD monomethoxypolyethylene glycol (mPEG) molecule. The mPEG is covalently bound 
to the N-terminal methionyl residue of filgrastim. 
The proposed clinical development program is designed to establish the safety and efficacy 
of HSP-130 as supportive care to decrease the incidence of infection in subjects with 
non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a 
clinically significant incidence of febrile neutropenia and to reduce the duration of 
neutropenia in patients with non-myeloid malignancies treated with 
cytotoxic/myelosuppressive agents. 
 
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1.2 
Investigational Medicinal Products 
The Investigational Medicinal Product, HSP-130, is a pegylated recombinant human 
methionyl G-CSF, also referred to as pegylated filgrastim. It is a conjugate of filgrastim and 
a 20 kD mPEG molecule. The mPEG is covalently bound to the N-terminal methionyl 
residue of filgrastim. For this study, 3 mg or 6 mg will be administered subcutaneously. If 
12 mg of HSP-130 is determined to be appropriate to study, the 12 mg dose will be 
administered subcutaneously, as 2 concurrent injections of 6 mg on the same arm separated 
by approximately 2 to 3 inches. 
1.3 
Non-clinical Data 
The nonclinical studies to support this Phase 1-2 clinical study have been completed and 
results summary is provided in the Investigational Brochure. 
1.4 
Clinical Experience 
This is the first human study to be conducted with HSP-130. There is no clinical experience 
with HSP-130. 
1.5 
Rationale for the Study 
1.5.1 
Design Features 
This is an open-label parallel group study characterizing the PD, PK, and safety of HSP-130 
in subjects with non-distantly metastatic (non-Stage IV) breast cancer who have not 
previously received chemotherapy at any point prior to enrollment in this study 
(ZIN-130-1504). 
There are two aspects of the study. In the initial part of the study, 6 subjects will be 
sequentially enrolled to receive HSP-130 treatment (3 mg or 6 mg by SC injection) without 
concomitant or background chemotherapy. This treatment setting will, therefore, be referred 
to as Cycle 0. Patients in Cycle 0 will receive HSP-130 during the period between biopsy and 
definitive surgery. 
Hospira’s rationale for choosing this setting includes optimizing the homogeneity of the 
study population. Factors potentially causing heterogeneity in the post-operative setting 
include: 
• Variability in the postoperative clinical course of patients  
• Known postoperative immunosuppression of variable degrees and duration  
• Potential perioperative variable effects of endogenous G-CSF  
Advice from experts in the field and review of published data has indicated that a period of 
approximately 1-1.5 months is not inconsistent with real world treatment intervals between 
biopsy and surgery. The post-biopsy/pre definitive surgery approach will, per protocol, not 
exceed 44 days. This maximum duration is based on a protocol-defined maximum of 14 days for 
screening, 20 days of study assessments, and the Day 30 (±2) Follow-up Visit. Further, with a 
 
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cooperative partnership between the surgeon(s) and principal investigator, this period might be 
further reduced. 
The second group of subjects will receive up to 4 cycles of HSP-130, with concomitant 
background chemotherapy. Patients in Cycles 1-4 will receive HSP-130 after definitive surgery. 
Chemotherapy will consist of every 3 week taxane/cyclophosphamide-based regimen, i.e., 
docetaxel, doxorubicin and cyclophosphamide (TAC). 
The initial component of the study with patients receiving HSP-130 at doses of 3 mg and 
6 mg without concomitant background chemotherapy is based on the considerations of 
patient safety. Based on the preponderance of published non-clinical and clinical data for the 
class of pegylated filgrastim, it is most likely that a dose of 3 mg could be sub-therapeutic. 
Both ANC and CD34+ will be assessed to address aspects of the known effect of pegylated 
filgrastim as a class on demargination of neutrophils as well as effect on the marrow, 
respectively. 
A variety of both fixed and weight-based doses was evaluated in the development of 
US-approved Neulasta (20). The approved dose of 6 mg US-approved Neulasta provided 
adequate production of neutrophils and hence weight-based dosing was not required (1), (20), 
(21). 
Assessment of PD and PK parameters after single and multiple doses of HSP-130 at 
3 ascending doses (3 mg, 6 mg or 12 mg, with the latter only if agreed to after data review at 
3 and 6 mg as detailed in Section 6.3.2.) will provide an adequate separation in doses to 
characterize the exposure/response sufficiently to support dosing recommendations in future 
clinical studies. 
Based on the dose-response curve published by B. Yang and A. Kido (1), the average 
concentration (Cav) of pegfilgrastim (calculated from the time of pegfilgrastim administration 
to the time of ANC nadir) for the 6 mg dose was 72 ng/mL, which corresponds to 90% of 
maximum response (EC90). For a 3 mg dose, the estimated Cav was about 21 ng/mL, which 
corresponds approximately 70% of maximum response (EC70). The expected response for a 
3 mg dose (EC70) is 77.8% of that from a 6 mg dose (EC90). It is expected that approximately 
30% of patients receiving 3 mg of pegfilgrastim would have a Cav value below the EC50 
value. Because the dose of 3 mg of HSP-130 is potentially sub-therapeutic in breast cancer 
patients, this dose will be tested in Cycle 0 without chemotherapy first. If the PD response 
(ANC and/or CD34+) of 3 mg HSP-130 and 6 mg HSP-130 in Cycle 0 indicate that the 3 mg 
dose level is sub-therapeutic, the 3 mg dose level will not be included in Cycles 1-4 
assessment. This design future will ensure that no patient with chemotherapy will be treated 
with sub-therapeutic dose of HSP-130. 
As noted above, the second component of the ZIN-130-1504 study includes up to 4 cycles of 
HSP-130, with concomitant background chemotherapy. The basis for the selection of breast 
cancer for the current Phase 1-2 study in patients is multifactorial and includes the large 
clinical trial experience with pegylated filgrastim in breast cancer (22). 
 
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1.5.2 
Study Population 
Female, chemotherapy-naïve, non-distantly metastatic (non-Stage IV) breast cancer subjects 
aged ≥ 18 years will be selected for this study as an appropriate population to assess the PD, 
PK and safety properties of HSP-130. Study population is limited to women for this Phase 
1-2 study based on the small total population numbers (approximately 36 to 48) and need for 
adequate homogeneity to inform dose selection for Phase 3 superiority and non-inferiority 
studies. 
1.5.3 
Dosing Regimen and Treatment Duration 
Subjects receiving HSP-130 during Cycle 0 will receive a single dose of HSP-130 (3 mg or 
6 mg) and be in the study for approximately 30 (± 2) days and will not receive concomitant 
background chemotherapy. 
Subjects receiving HSP-130 during Cycles 1-4 will receive up to 4 doses of HSP-130 in the 
context 4 cycles of chemotherapy (≥ 21 days per cycle). Exclusive of chemotherapy-related 
treatment delays, these subjects will participate in the study for approximately 94 days 
(including Follow-up Visit). 
1.5.4 
Selection of Pharmacodynamic Endpoints 
The mechanism of stimulation of the production of neutrophils by G-CSFs is well 
understood. The G-CSF acts by binding to G-CSF receptors located on the cell surface of the 
whole neutrophil lineage, resulting in stimulated proliferation, differentiation, commitment, 
and end cell functional activation. Endogenous G-CSF is known to stimulate proliferation of 
the mitotic cells, to reduce the maturation time of the non-mitotic cells in the bone marrow 
and to prolong the life-span and enhance the function of mature neutrophils. Endogenous 
G-CSF is produced by different cell types including macrophages, monocytes, fibroblasts, 
stromal cells in bone marrow, and endothelial cells (7). Both filgrastim and pegfilgrastim act 
on hematopoietic cells by binding to specific cell surface receptors, which in turn stimulate 
proliferation, differentiation and end cell functional activation to produce neutrophils (19), 
(23). 
ANC is a direct measure of the therapeutic effect measured in the treatment of neutropenia. 
Assessment of CD34+ count in Cycle 0 will address any differences in marrow response 
between 6 mg and 3 mg (a potentially sub-therapeutic dose) to limit the risk of treatment of 
subjects receiving myelosuppressive chemotherapy in Cycles 1-4 determined to have risk of 
≥ 20% for febrile neutropenia (FN). 
Cycle 0: 
Area under the effect curve for ANC (AUECANC) was selected as the primary endpoint for 
Cycle 0 because the production of neutrophils is the primary therapeutic effect measured in 
the treatment of neutropenia. Evaluation of ANC as a measure of PD for pegylated filgrastim 
is well established via clinical trials of pegfilgrastim (1), (23), (24), (25). Area under the 
effect curve is a more appropriate parameter than any measure at a single time because it 
assesses the overall response to the administered dose. 
 
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The sampling schedule for ANC and CD34+ count is of sufficient density and duration to 
adequately characterize the PD response following single and multiple dose administration of 
HSP-130. The AUECANC from baseline through Day 20 after single dose provides a 
sufficient duration to characterize PD response to HSP-130 (1), (24), (25). 
Secondary PD parameters include maximum effect for ANC (ANC_Emax), time of maximum 
effect for ANC (ANC Tmax), area under the effect curve for CD34+ (AUECCD34+), maximum 
effect for CD34+ count (CD34+_Emax), time of maximum effect for CD34+ count (CD34+ 
Tmax). 
Cycles 1-4: 
Duration of severe neutropenia (DSN) was selected as the PD parameter for Cycles 1-4 to 
characterize the effect of HSP-130 in decreasing the neutropenic effect of myelosuppressive 
chemotherapy. Duration of severe neutropenia is defined as days with grade 4 neutropenia 
(ANC < 0.5 × 109/L). 
Primary PD parameter includes DSN in Cycle 1. Secondary PD parameters include DSN in 
Cycle 4, ANC nadir concentration, time of nadir concentration, area under the effect curve 
(AUEC), incidence of febrile neutropenia, defined as tympanic or axillary body temperature 
> 38.5°C for > 1 hour and ANC < 1.0 x 109/L, incidence of severe neutropenia (grade 4, 
ANC < 0.5 x 109/L) and time to ANC recovery (the first day with ANC ≥ 2.0 x 109/L after 
any day with ANC < 2.0 x 109/L) in Cycle 1 and Cycle 4. 
1.5.5 
Selection of Pharmacokinetic Endpoints 
The sampling schedule for PK measurement will fully define the PK characteristics of the  
3 doses of HSP-130 administered. 
Cycle 0: 
The primary PK endpoints are area under the serum HSP-130 versus time curve from the 
time of dose administration to time infinity (AUC0-∞) and the maximum observed serum 
HSP-130 concentration (Cmax). The secondary PK parameters include area under the serum 
HSP-130 versus time curve from the time of dose administration to the time of last 
measurable concentration (AUC0-t), the time of maximum serum HSP-130 concentration 
(Tmax), elimination half-life (t1/2), elimination rate constant (λz) and apparent clearance (CL). 
The sampling through Day 20 provides sufficient samples to calculate AUC0-∞, AUC0-t and 
Cmax for all the dose levels planned (1), (24), (25). 
Cycles 1-4: 
The primary PK endpoints are AUC0-t and Cmax. The secondary PK endpoints include 
AUC0-∞, Tmax, t1/2, λz, and CL. The sampling through Day 20 provides sufficient samples to 
calculate AUC0-t, AUC0-∞, and Cmax for all the dose levels planned. 
 
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1.6 
Risk/Benefit 
Chemotherapy naïve, non-distantly metastatic (non-Stage IV) breast cancer subjects with age 
≥ 18 years will be enrolled for this study. It is expected that subjects will be getting the 
therapeutic benefit due to HSP-130 while participating in the study. 
The general pharmacologic class risks associated with use of G-CSFs are informed by the 
US-approved Neupogen® Package Insert and US-approved Neulasta Package Insert and 
EU-approved Neulasta Summary of Product Characteristics include but are not limited to 
allergic reactions including systemic symptoms involving at least 2 body systems of skin 
(rash, urticaria, facial edema), respiratory (wheezing, dyspnea) and cardiovascular 
(hypotension, tachycardia); splenic rupture which can present as left upper abdominal and/or 
shoulder tip pain with enlarged spleen or splenic rupture; acute respiratory distress syndrome 
(ARDS) presenting with fever, lung infiltrates or respiratory distress as this may be 
secondary to an influx of neutrophils to sites of inflammation in the lungs; sickle cell crisis in 
subjects with sickle cell disorders; leukocytosis and immunogenicity. Additional potential 
risks include cutaneous vasculitis, thrombocytopenia, capillary leak syndrome and cytokine 
release syndrome (19), (23). 
A more detailed description of the side effects with the use of pegylated G-CSF is described 
in the US-approved Neulasta Package Insert and the EU-approved Neulasta Summary of 
Product Characteristics (See Appendix H and Appendix F, respectively) (23). 
 
 
 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objectives and Endpoints 
2.1.1 
Primary Objective (s)  
Cycle 0: 
• To characterize the PD response of ANC and CD34+ count to HSP-130 at doses of 
3 mg and 6 mg when administered as a single SC dose without chemotherapy to 
determine whether it is appropriate to study multiple doses of 3 mg with the context 
of background chemotherapy 
Cycles 1-4: 
• To characterize the PD response of duration of severe neutropenia (DSN) in Cycle 1 
to HSP-130 over a range of doses when administered as single and multiple SC doses 
2.1.2 
Pharmacodynamic Endpoints 
The PD endpoints are based on the following variables: 
Cycle 0: 
• 
Primary Variable: Area under the effect curve for ANC (AUECANC) 
• 
Secondary Variables: Maximum effect for ANC (ANC_Emax), time of maximum 
effect for ANC (ANC Tmax), area under the effect curve for CD34+ (AUECCD34+), 
maximum effect for CD34+ count (CD34+_Emax), time of maximum effect for CD34+ 
count (CD34+ Tmax) 
The PD variables will be calculated using non-compartmental methods. 
Cycles 1-4: 
• 
Primary Variable: Duration of severe neutropenia (DSN). DSN is defined as days 
with grade 4 neutropenia (ANC < 0.5 x 109/L) in Cycle 1 
• 
Secondary Variables: DSN in Cycle 4. ANC nadir concentration, time of nadir 
concentration, area under the effect curve (AUEC), incidence of FN, defined as 
tympanic or axillary body temperature > 38.5°C for > 1 hour with 
ANC < 1.0 x 109/L, incidence of severe neutropenia (grade 4, ANC < 0.5 x 109/L) 
and time to ANC recovery (the first day with ANC ≥ 2.0 x 109/L after any day with 
ANC < 2.0 x 109/L) in Cycle 1 and Cycle 4 
The PD variables will be calculated using non-compartmental methods. 
 
 
 
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2.2 
Secondary Objectives and Endpoints 
2.2.1 
Secondary Objective (s) 
Cycle 0: 
• To characterize the PK of HSP-130 at doses of 3 mg and 6 mg when administered as 
a single SC dose without background chemotherapy 
• To characterize the safety of HSP-130 at doses of 3 mg and 6 mg when administered 
as a single SC dose without background chemotherapy 
Cycle 1-4: 
• To characterize the PD response of ANC to HSP-130 in Cycles 1 and 4 over a range 
of doses when administered as single and multiple SC doses 
• To characterize the PK of HSP-130 in Cycles 1 and 4 over a range of doses when 
administered as single and multiple SC doses 
• 
To characterize the safety of HSP-130 over a range of doses when administered as 
single and multiple SC doses 
2.2.2 
Pharmacokinetic Endpoints 
The PK endpoints are based on the following variables: 
Cycle 0: 
• 
Primary Variables: Area under the serum HSP-130 versus time curve from the time 
of dose administration to time infinity (AUC0-∞) and the maximum observed serum 
HSP-130 concentration (Cmax) 
• 
Secondary Variables: Area under the serum HSP-130 versus time curve from the 
time of dose administration to the time of last measurable concentration (AUC0-t), the 
time of maximum serum HSP-130 concentration (Tmax), elimination half-life (t1/2), 
elimination rate constant (λz), and apparent clearance (CL) 
The PK variables will be calculated using non-compartmental methods. 
Cycles 1–4: 
• 
Primary Variables: AUC0-t and Cmax 
• 
Secondary Variables: AUC0-∞, Tmax, t1/2, λz, and CL 
The PK variables will be calculated using non-compartmental methods. 
 
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2.3 
Safety Variables 
Enrolled subjects who receive at least one dose of HSP-130 will be included in the safety 
analyses. The safety variables to be assessed include adverse events (AEs), AEs of special 
interest, laboratory assessments and electrocardiogram (ECG) at Follow-up Visit at study end 
and as clinically indicated, vital signs, and physical examination. Please refer to Section 6.3.2 
for additional detail regarding safety assessments and dose escalation criteria. 
Cycle 0: 
Subjects will be chemotherapy naïve and will not be receiving background chemotherapy 
during Cycle 0. Safety variables to be assessed include AEs, including AEs of special 
interest, laboratory assessments and including ECG at Follow-up Visit at study end and as 
clinically indicated, vital signs, and physical examination. 
Cycles 1-4: 
To begin full-dose chemotherapy on Day 1 of the next cycle (≥ Day 21 of the previous 
cycle), ANC must have recovered to ≥ 1.5 x 109/L and platelet counts to ≥ 100 x 109/L. If 
these requirements are not met, postponement of the following cycle for up to 2 weeks will 
be acceptable. Both ANC and platelets will be determined on Day 15 and on Day 20 of 
Cycles 1-4 by a central laboratory so that results were available at the beginning of the next 
cycle. 
The following are generally accepted approaches to modification of chemotherapy regimens 
to be following in the context of febrile neutropenia or severe or prolong neutropenia with or 
without fever. In subjects who experience FN and/or ANC < 0.5 x 109/L for > 1 week, severe 
or cumulative cutaneous reactions, or severe (grade 3 or 4) peripheral neuropathy during 
therapy, the chemotherapy timing and dose  will be modified as deemed appropriate by the 
treating physician. Changes in patients TAC chemotherapy regimen will be determined by 
the patients treating physician in the context of known TAC toxicity profile and management. 
Subjects who withdraw prior to Cycle 2 may be replaced to support the full complement 
subjects (minimum of 8 evaluable subjects) for primary endpoint data generation for Cycle 1. 
It is recommended that rescue management for subjects who develop FN during the study be 
consistent with several recent publications (2), (3), (4) and recent Cochrane review (5). 
Management of FN should also include consideration of locale-driven susceptibility patterns. 
 
 
 
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2.4 
Anti-HSP-130 Antibody Assessment 
Cycle 0: 
Blood samples (7.0 mL) for anti-HSP-130 antibodies assessment will be collected prior to 
dose on Day 1 (prior to dose), on Day 14, and on Day 20. 
Cycles 1-4: 
Blood samples (7.0 mL) for anti-HSP-130 antibodies assessment will be collected on Day 2 
(prior to HSP-130 dose) and on Day 20 in Cycles 1 and 4. 
2.5 
Additional Assessments 
2.5.1 
Performance Status 
Performance status (PS) is an assessment of a subject’s level of function and capability of 
self-care and has repeatedly been shown to be an important prognostic factor for survival in 
several major cancer forms, e.g., breast cancer (26), ovarian cancer (27), small cell lung 
cancer (28), and non-small cell lung cancer (29).  As a result, PS is consistently integrated 
into oncology clinical trial. The most widely used are Karnofsky’s Scale of PS (30) based on 
a scale of 0 to 100 and the simpler scale, the Zubrod (also known as WHO or Eastern 
Cooperative Oncology Group [ECOG]) Scale of PS (31), (32). The WHO scale will be used 
in this protocol and will be assessed at each study visit per the Schedule of Study Activities 
in Tables 1-3 and is defined in Table 5. 
Table 5. 
The WHO/Zubrod/ECOG Scale 
Grade 
Explanation of Activity 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair 
5 
Dead 
 
 
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2.5.2 
Clinical Index of Stable Febrile Neutropenia  
Chemotherapy-induced FN is a frequent, potentially life-threatening toxicity that predisposes 
patients with cancer to serious infections and limits the delivery of optimal therapeutic doses 
of chemotherapy. The rate of major complications in the context of FN is approximately 25% 
to 30%, and mortality is as high as 11% in some patient groups (33). Appropriate treatment 
of patients with FN also includes prevention of over-treatment of low-risk episodes of FN 
with resultant patient-centric stress, implications of antimicrobial over-treatment and burden 
to healthcare systems (34). 
The most widely validated prognostic tool used to select low-risk patients with FN is the 
Multinational Association for Supportive Care in Cancer (MASCC) score, which has been 
shown to be more accurate than the Talcott classification (35), (36), (37). 
As has been pointed out by Carmona-Bayonas et al (2015) (2), these models are not specific 
to patients with solid tumors. In addition, the ability of the MASCC score to predict serious 
complications is not optimal, because they occur in up to 9% to 15% of patients predicted to 
be at low risk (35), (38). 
In response to this perceived need, Carmona-Bayonas et al (2) developed the Clinical Index 
of Stable Febrile Neutropenia (CISNE), with 6 explanatory variables associated with serious 
complications: WHO performance status ≥ 2 (2 points), chronic obstructive pulmonary 
disease (1 point), chronic cardiovascular disease (1 point), mucositis of grade ≥ 2 (National 
Cancer Institute Common Toxicity Criteria; 1 point), monocytes < 200 per µL (1 point), and 
stress-induced hyperglycemia (2 points). These factors were integrated into a score ranging 
from 0 to 8, which classifies patients into 3 prognostic classes: low (0 points), intermediate 
(1 to 2 points), and high risk (≥ 3 points). The validation study was published in early 2015 
based on the outcomes of 1,133 patients recruited from Sept 2012 to July 2014 with 
seemingly stable FN from 25 hospitals (24 Spain, 1 Chile). 
Complication, mortality, and bacteremia rates by risk category are summarized in Table 6. 
Areas under the receiver operating characteristic curves in the validation subset were 0.652 
(95% confidence interval [95% CI], 0.598 to 0.703) for Talcott, 0.721 (95% CI, 0.669 to 
0.768) for MASCC, and 0.868 (95% CI, 0.827 to 0.903) for CISNE (P = 0.002 for 
comparison between CISNE and MASCC). 
With a cutoff of ≥ 3 points, CISNE showed good discriminatory power to predict major 
complications, with the following parameters: sensitivity, 77.7%; specificity, 78.4%; Positive 
Predictive Value (PPV), 36.1%; Negative Predictive Value (NPV), 95.7%; Positive 
likelihood ratio (pLR), 3.6; and Negative likelihood ratio (nLR), 0.28. 
The use of the CISNE is potentially and important tool in decision making in patient 
experiencing febrile neutropenia and will be assessed prospectively in the study per the 
Schedules of Study Activities in Tables 1-3, i.e., on Days 1, 7, 20, and 30 (Follow-up Visit) 
for subjects in Cycle 0; on Days 1 and 8 for Cycles 1 and 4; and on Day 2 for Cycles 2 and 3 
based on country-specific translation availability. 
 
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Table 6. 
Outcomes by CISNE by Risk Categories (n = 1,133) 
Risk Category (Class) 
Training Subsets 
Validation Subsets 
Complications 
 
 
I (0 points) 
1.1 
1.1 
II (1-2 points) 
6.1 
6.2 
III (≥ 3 points) 
32.5 
32.5 
Mortality 
 
 
I (0 points) 
0.0 
0.0 
II (1-2 points) 
1.6 
0.0 
III (≥ 3 points) 
4.3 
3.1 
Bacteremia 
 
 
I (0 points) 
3.2 
9.1 
II (1-2 points) 
9.7 
9.0 
III (≥3 points) 
17.6 
15.5 
 
2.5.3 
Functional Assessment of Cancer Therapy – Neutropenia 
The Functional Assessment of Cancer Therapy - Neutropenia (FACT- N) is widely used and 
validated self-report instrument to assess neutropenia-specific concerns and health-related 
quality of life (HRQOL) (39), (40). Tools to assess HRQOL are incorporated less commonly 
in Phase 1 or 2 studies than in Phase 3 studies. However, this will be assessed in the current 
study per the Schedule of Study Activities in Tables 1-3, i.e., on Days 1, 20, and 30 
(Follow-up Visit) for subjects in Cycle 0; on Day 1 and at Follow-up Visit for Cycles 1 and 
4; and on Day 2 for Cycles 2 and 3 to help assess the variables included in the subject 
assessment based on first use in humans of this specific pegylated filgrastim. These will be 
assessed based on country-specific translation availability. 
 
 
 
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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is an open-label, parallel group study characterizing the PD, PK, and safety of HSP-130 
in subjects with non-distantly metastatic (non-Stage IV) breast cancer who have not 
previously received chemotherapy at any point prior to enrollment in this study. The dose 
groups of 3 mg, 6 mg, and 12 mg for HSP-130 are selected for the purpose of the study. 
However, 12 mg will only be studied, after discussion with the FDA, as defined in Section 
6.3.2. 
There are two aspects of the study. In the initial part of the study, 6 subjects will be 
sequentially enrolled to receive HSP-130 treatment (3 mg or 6 mg by SC injection) without 
concomitant or background chemotherapy. This treatment setting will, therefore, be referred 
to as Cycle 0. Patients in Cycle 0 will receive HSP-130 during the period between biopsy and 
definitive surgery. 
The second group of subjects will receive up to 4 cycles of HSP-130, with concomitant 
background chemotherapy. Patients in Cycles 1-4 will receive HSP-130 after definitive surgery. 
Chemotherapy will consist of every 3 week taxane/cyclophosphamide-based regimen, i.e., 
TAC. 
Specifics of these two groups are addressed below. 
Subjects in Cycle 0: 
Subject eligibility will be determined during a 14-day Screening Period. Eligible subjects 
will be enrolled sequentially to each of the HSP-130 dose groups as follows: 
Regimen A: HSP-130, 3 mg, single SC injection in the deltoid region (n = 6) 
Regimen B: HSP-130, 6 mg, single SC injection in the deltoid region (n = 6) 
Dose escalation from Regimen A to B will be based on safety assessments in the first 
5 evaluable subjects receiving Regimen A. This will include assessment of vital signs, 
concomitant medications, laboratory assessments including chemistry and hematology 
(complete blood count [CBC] and platelets), ECG, physical exam, and any AEs occurring 
post-dose administration through Day 30. The specific safety criteria for assessment for dose 
escalation are listed in Section 6.3.2 of the protocol. If, based on these assessments, there is 
no contraindication for dose escalation, screening for the subsequent dose level (Regimen B) 
can be initiated. 
In Cycle 0, Day 1 is the day that the subject receives HSP-130. Subjects obtain a baseline 
assessment of ANC and CD34+ count on Day 1 prior to receipt of HSP-130. Subjects will 
return for ANC, CD34+ measurement, and PK assessment for up to a maximum of 7 visits 
after HSP-130 dosing. 
 
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After completion of Cycle 0, each of the subjects in these dosing groups will have completed 
their participation in assessment of HSP-130. The site will be offered reimbursement for 
treatment with EU-approved Neulasta in accordance with local standard of care by the 
Investigator with subsequent non-study chemotherapy regimen. 
Assessment of Regimen A (3 mg) for Cycles 1-4 will be conducted as follows: 
Based on the dose-response curve published by B. Yang and A. Kido (1), the average 
concentration (Cav) of pegfilgrastim (calculated from the time of pegfilgrastim administration 
to the time of ANC nadir) for the 6 mg dose was 72 ng/mL, which corresponds to 90% of 
maximum response (EC90). 
For a 3 mg dose, the estimated Cav was about 21 ng/mL, which corresponds approximately 
70% of maximum response (EC70). The expected response for a 3 mg dose (EC70) is 77.8% 
of that from a 6 mg dose (EC90). 
It is expected that approximately 30% of subjects receiving 3 mg of pegfilgrastim would 
have a Cav value below the EC50 value. Because the dose of 3 mg of HSP-130 is potentially 
sub-therapeutic in breast cancer patients, this dose will be tested in Cycle 0 without 
chemotherapy first. 
If the PD response (ANC and/or CD34+) of 3 mg HSP-130 and 6 mg HSP-130 in Cycle 0 
indicate that the 3 mg dose level is sub-therapeutic, the 3 mg dose level will not be included 
in Cycles 1-4 assessment. This design feature will ensure that no subject with chemotherapy 
will be treated with sub-therapeutic dose of HSP-130. 
If, however, the individual PD measurement (ANC and/or CD34+) of the treatment with 
HSP-130 3 mg in Cycle 0 is commensurate with that of 6 mg, as defined by the protocol, 
then treatment with Regimen A with background chemotherapy will be initiated. 
Subjects in Cycles 1-4: 
When enrollment of the 6 subjects receiving Regimen B in Cycle 0 is completed, an 
additional 12 subjects will be enrolled on Regimen B and entered in Cycles 1-4 as defined 
below. Eligible subjects will be enrolled sequentially to each of the HSP-130 dose groups as 
follows: 
Regimen B: HSP-130, 6 mg, single SC injection in the deltoid region, at least 24 hours 
after administration of chemotherapy in Cycle 1, Cycle 2, Cycle 3, and Cycle 4 (n=12). 
Potential Regimen A (3 mg) with background chemotherapy: Inclusion of this cohort 
will be based on assessment of comparability between Regimens A and B in Cycle 0 for 
ANC and CD34+ as defined above. If performed, this regimen will be HSP-130, 3 mg, 
single SC injection in the deltoid region, at least 24 hours after administration of 
chemotherapy in Cycle 1, Cycle 2, Cycle 3, and Cycle 4 (n=12), as appropriate. 
While noted in the protocol schema which is included for completeness, the 12 mg cohort 
will not be initiated until Hospira has analyzed the data from the Cycle 0 for 3 mg and 6 mg 
 
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cohorts and the Cycles 1-4 for 6 mg cohort (and 3 mg cohort, if performed) and reviewed the 
results with the FDA. Escalation to 12 mg will only proceed if the exposure pattern of the 
PK/PD responses suggests that higher doses are required. Please see section 6.3.2 for 
additional details. 
During Cycles 1-4 for each of the regimens, subjects will receive treatment with HSP-130 at 
24 hours after administration of chemotherapy (Day 2). Subjects will return for ANC 
measurement and PK assessment for up to an additional 7 visits after dosing. 
Subjects will return for a Follow-up Visit 30 (±2) days after the dose of HSP-130 in Cycle 4. 
3.2 
Number of Sites and Subjects 
Subjects will be enrolled at hospital sites (approximately 10 sites) within Europe. 
A total of 24-36 patients will be enrolled initially; a further 12 patients totaling 
approximately 36-48 patients will be treated if the 12 mg cohort is enrolled, as defined in 
Section 6.3.2. 
• The number of 24 patients includes 12 patients in Cycle 0 and 12 patients in the 
Cycles 1-4 6 mg cohort. 
• The number of 36 patients includes the additional 12 patients if the second 3 mg cohort is 
included in the Cycles 1-4 part of the study. 
• The number of 48 patients includes the potential for 12 patients in the 12 mg cohort if, 
after review of the data in the up to 36 patients with the FDA, a decision is jointly made 
based on the exposure pattern of the PK/PD responses that higher doses are required. 
Approximately 12 subjects will be enrolled into two cohorts to receive ascending doses of 
HSP-130 (6 subjects on Regimen A [3 mg] and 6 subjects on Regimen B [6 mg]) without 
background chemotherapy. 
Twelve subjects will be enrolled into 6 mg cohort in the setting of background 
chemotherapy. As mentioned, enrollment in a 12 mg cohort will not be initiated until criteria 
addressed in section 6.3.2 are met. 
An additional 12 subjects will be enrolled into Regimen A (3 mg) as defined in Section 1.5.1. 
3.3 
Estimated Study Duration 
Subjects receiving HSP-130 during Cycle 0 will receive a single dose of HSP-130 (3 mg or 
6 mg) and be in the study for approximately 30 (± 2) days and will not receive concomitant 
background chemotherapy. Patients in Cycle 0 will receive HSP-130 during the period between 
biopsy and definitive surgery. 
Subjects receiving HSP-130 during Cycles 1-4 will receive up to 4 doses of HSP-130 in the 
context of 4 cycles of chemotherapy (≥ 21 days per cycle). Patients in Cycles 1-4 will receive 
HSP-130 after definitive surgery. Each of these subjects will have treatment duration, if there 
 
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are no chemotherapy-related treatment delays, of approximately 108 days (including 
Screening Period and Follow-up Visit).  
 
 
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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Subjects will undergo screening procedures within 14 days prior to initial HSP-130 
administration. Subjects must meet all of the inclusion and none of the exclusion criteria to 
be enrolled in the study. 
4.2 
Inclusion Criteria 
A subject will be eligible for study participation if all of the following criteria are met at 
Screening: 
1. Is informed, has been given ample time and opportunity to read about participation in the 
study and has signed and dated the written informed consent form approved by an 
Independent Ethics committee (IEC) prior to any study related activities 
2. Females ≥ 18 years 
3. Histologically confirmed and documented invasive breast cancer 
4. Breast cancer without evidence of distant metastases (non-Stage 4) based on staging 
work-up  
5. Chemotherapy naïve, who have not received chemotherapy in the neoadjuvant setting and 
who are candidates for chemotherapy in the adjuvant setting of 
taxane/cyclophosphamide-based regimen, i.e., TAC, as background chemotherapy 
6. Zubrod/WHO/ECOG performance status ≤ 2 
7. Adequate bone marrow, hepatic, and renal function reserve as evidenced by: 
a. Hemoglobin ≥ 10 mg/dL 
b. ANC ≥ 1.5 x 109/L 
c. Platelet count of ≥ 100 x 109/L 
d. Total bilirubin ≤ 2 mg/dL 
e. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 
≤ 3 x the upper limit of normal (ULN) of the reference lab 
f. Serum creatinine of ≤ 1.5 x ULN for reference lab or estimated glomerular 
filtration rate (eGFR) of ≥ 60 mg/min 
8. Body mass index (BMI) of 19 to 40 kg/m2, inclusive 
 
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9. Subjects of childbearing potential, and their partners, agree to pregnancy prevention 
throughout the duration of the study (through the Follow-up Visit). Specific type of 
pregnancy prevention should be discussed with, and acceptable to, the treating oncologist 
in the context of the tumoral hormone receptor status. Subjects and their partners must 
agree to use of an effective method of contraception, to avoid impregnation of females 
throughout the course of the study 
Medically acceptable forms of birth control can include, with approval of the treating 
physician: 
a. Barrier methods (condom or diaphragm with spermicide) 
b. Intrauterine device (IUD) 
c. Hormone contraceptives (such as oral [pill], injection, skin patch, implant, 
cervical ring) 
d. Subjects using oral contraceptives must be on a stable regimen for at least 
3 months prior to Screening. Sexually active subjects must use contraception 
while on HSP-130 from admission to the final Follow-up Visit 
10. Able to understand verbal or written instructions and comply with all study requirements, 
to communicate effectively with study personnel and is available for the planned duration 
of the study 
4.3 
Exclusion criteria 
A subject will NOT be eligible for study participation if any of the following criteria are met 
at Screening: 
1. Previous G-CSF exposure, including filgrastim, lenograstim, pegfilgrastim, 
lipegfilgrastim, granulocyte/macrophage colony stimulating growth factor (GM-CSF), or 
any other branded or biosimilar G-CSF 
2. Prior autologous stem cell harvest of any type 
3. Drug sensitivity, allergic reaction, or known hypersensitivity or idiosyncratic reaction to 
E. coli-derived proteins, filgrastim, other G-CSFs, or pegylated agents 
4. Known hypersensitivity to docetaxel, polysorbate 80, or doxorubicin 
5. For subjects receiving doxorubicin, no concurrent use of inhibitors and inducers of 
CYP3A4, CYP2D6, and/or P-gp or with trastuzumab due to increased risk of cardiac 
dysfunction 
6. Chemotherapy other than that included in this study (taxane/cyclophosphamide-based 
regimen, i.e., TAC) or neoadjuvant chemotherapy; or known immunosuppressive agents 
including chronic oral corticosteroid use, or radiation therapy within 4 weeks of first dose 
 
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of HSP-130, prior bone marrow or stem cell transplantation, or malignancy within 
5 years 
7. Known HER2+ (overexpressing breast cancer) 
8. Known triple negative (estrogen receptor-negative, progesterone receptor-negative and 
HER2-negative) breast cancer 
9. ≥ Grade 2 underlying neuropathy 
10. Current diagnosis of active tuberculosis or other severe infection, such as sepsis, 
abscesses or opportunistic infections 
11. Treatment with systemically active antibiotics within 72 hours before chemotherapy 
12. Known infection with HIV 
13. Known sickle cell disease 
14. Known severe persistent drug-induced myelosuppression 
15. New York Heart Association (NYHA) class III or IV heart failure, severe uncontrolled 
cardiac disease (unstable angina, clinically significant ECG abnormalities) or MI within 
the previous 6 months before the first administration of HSP-130 
16. Any malignancy other than breast cancer, with exception of adequately treated squamous 
or basal cell carcinoma of the skin or cervical carcinoma in situ, within 5 years before the 
first administration of the HSP-130 
17. Current or recent treatment (within 30 days before the first administration of the 
HSP-130) with any other investigational medicinal product 
18. Pregnancy or lactation; Subjects planning to be pregnant or to breastfeed before, during, 
or within 12 months after administration of the HSP-130 are not permitted to enroll in the 
study 
19. Received a live, live-attenuated, or non-live vaccine within 4 weeks before the first 
administration of the HSP-130 
20. Patient has evidence of any other coexisting disease or medical or psychological 
condition, metabolic dysfunction, physical examination finding or clinical lab finding 
giving reasonable suspicion of a disease or condition that contraindicated the use of an 
HSP-130, or patient is high risk for treatment complication 
4.4 
Inclusion of Subjects Incapable of Informed Consent 
Subjects incapable of giving informed consent will not be enrolled in this study. 
 
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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
4.5 
Recruitment Methods 
Recruitment methods that will be employed include, but are not limited to, advertising, and 
use of the clinical unit database to identify potential candidates for this study. 
 
 
 
Page 56 of 145 
 


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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
5.1.7 
Dosage, Preparation, Administration, Schedule, and Compliance  
The doses of HSP-130 to potentially be administered in this study are 3 mg, 6 mg and 12 mg. 
Inclusion of the 12 mg dose will only occur as defined in Section 6.3.2. Each subject will 
receive one of the following: 3 mg, 6 mg [or 12 mg] of HSP-130 as SC injection on Study 
Day 1. Please refer to Section 3.1 for detailed description of the administration schedule. 
HSP-130 will be administered in the morning at approximately 8.00 on Day 1 in Cycle 0 and 
at 24 hours after chemotherapy in Cycle 1-4. HSP-130 will be administered by qualified 
medical personnel. The time of drug administration will be recorded to the nearest minute in 
each period. 
Before administration, HSP-130 formulation should be inspected visually for particulate 
matter. Only a solution that is clear and colorless to slightly yellow should be injected. 
Excessive shaking may aggregate pegylated G-CSF, rendering it biologically inactive. 
The syringe should be allowed to reach room temperature before injecting. 
For detailed instructions on preparation and proper use of HSP-130, see Pharmacy Manual. 
Treatment compliance will be ensured by the following study procedures: 
• HSP-130 will be administered by a qualified health care professional. 
• HSP-130 administration will be recorded in the source documents and entered in the 
appropriate section of the electronic Case Report Form (eCRF). Any problems with 
the injection will be recorded in the source documents and in the eCRFs. 
5.1.8 
Treatment of Overdose 
This is first use of HSP-130 in humans. The maximum amount of HSP-130 that can be safely 
administered has not been determined. Hence, a dose escalating design has been planned to 
evaluate the safety of the product in the previous dose before administering the next higher 
dose. 
As per Neulasta Package Insert, pegylated G-CSF overdosage can cause leukocytosis, which 
should be managed with discontinuation or reduction of pegylated-G-CSF dosage. The 
duration of leukocytosis ranged from 6 to 13 days. The effectiveness of leukapheresis in the 
management of symptomatic individuals with pegylated-G-CSF-induced leukocytosis has not 
been studied (23). 
5.2 
Subject Obligations 
In addition to the requirements of the study, subjects will also be required to participate in a 
Follow-up Visit 30 (± 2) days after HSP-130 administration in Cycle 4, as described in the 
Section 6.3.4. The subject must continue to comply with the protocol requirements from the 
time of final visit (Day 20) until the time of the Follow-up Visit (Day 30 [± 2]). 
 
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Protocol ZIN-130-1504  
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5.3 
Definition of End of Study 
The end of study is defined as the day the last subject completes the Follow-up Visit, 30 days 
after last dose of HSP-130, in Cycle 4 or is discontinued. 
 
 
 
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Protocol ZIN-130-1504  
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6 
TREATMENT PROCEDURES 
6.1 
Subject Informed Consent 
Prior to any study-related activities, an Institutional Review Board (IRB)/IEC approved 
Informed Consent Form (ICF) must be signed and personally dated by the subject. The 
format and content of the ICF and subject information sheet must be agreed upon by the 
Principal Investigator(s), appropriate IRB/IEC and Hospira and/or designee, and include as a 
minimum the elements of consent described in International Conference on Harmonization 
for Good Clinical Practice (ICH E6, GCP), and FDA 21CFR§50.25. The ICF should be 
available in the language of the potential subject. The risks and benefits of participating in 
the study will be explained by the study investigator/delegate and all questions asked by the 
subject will be addressed before the subject signs the ICF. The time and date of the informed 
consent process/discussion/signing taking place will be recorded in the source documents. 
It is the Investigator’s responsibility to obtain consent only after the subject has received an 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study, and before any study procedures are started. The subject should be given a copy of the 
IRB/IEC-approved ICF. The original copy of the signed and dated ICF must be retained in 
the clinic’s records, and is subject to inspection by representatives of Hospira, and/or 
representatives from regulatory authorities. An entry must also be made in the subject's dated 
source documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed and dated copy. Elements of Informed 
Consent are specified in Appendix C. 
6.2 
Study Activities 
6.2.1 
Subject Demographics 
Basic demographic information including date of birth, sex, ethnicity, and race will be 
recorded at the Screening visit. 
6.2.2 
Medical History 
A complete medical history, including alcohol, nicotine-containing product, and drug abuse 
histories, will be recorded at Screening. 
The medical history obtained on Screening will serve as the baseline for clinical assessment. 
6.2.3 
Prior and Concomitant Therapy Collection 
All medications (prescription and non-prescription drugs) taken within 7 days (or 
5 half-lives, whichever is longer) prior to Screening visit will be recorded at Screening, and 
at each study visit through end of the study. 
 
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Protocol ZIN-130-1504  
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All medications taken will be documented on the source document and recorded on the 
eCRF. 
6.2.4 
Physical Examination 
A physical examination will be performed at Screening and at the Follow-up Visit (after 
Cycle 0 and after Cycle 4) or upon subject discontinuation. Physical examination will 
specifically include physical assessment of the spleen. 
Height and weight, without shoes, will be measured at Screening only. 
The physical examination performed at Screening will serve as the baseline physical 
examination for clinical assessment. Any changes to or worsening of existing physical 
examination findings, or new abnormal physical examination findings after dosing will be 
recorded as AEs per the Investigator’s judgment. 
6.2.5 
Vital Signs 
Body temperature (tympanic or axillary), heart rate (sitting), blood pressure (sitting systolic 
and diastolic) and respiratory rate will be measured at Screening, at each study visit in 
Cycles 0-4 (at approximately the same time of each day at each visit) and at Follow-up Visit 
after Cycle 0 and after Cycle 4 or upon subject discontinuation. 
Vital signs should be measured pre-dose on the dosing day (Day 1 in Cycle 0; Day 2 in 
Cycles 1-4). Vital signs should be recorded prior to collection of blood samples for ANC 
measurement and PK assessment. The last available vital sign measurements prior to the start 
of HSP-130 will serve as the baseline measurements for clinical assessment. 
Blood pressure and pulse rate will be measured after the subject has been sitting at rest for at 
least 5 minutes. 
6.2.6 
12-Lead Resting ECG and Chest X-ray 
A 12-lead resting ECG will be obtained at Screening and at the Follow-up Visit after Cycle 0 
and after Cycle 4 or upon subject discontinuation and read by qualified site personnel. 
Chest X-ray will be obtained at Screening and read by qualified site personnel. 
6.2.7 
Adverse Event Monitoring 
Recording of any AEs will proceed as documented in Section 8 of this protocol. 
6.2.8 
Clinical Laboratory Tests 
Samples will be obtained for the central clinical laboratory tests (Clinical chemistry and 
Hematology) as outlined in Table 8 and in the Schedule of Study Activities (Tables 1-3). 
 
 
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Protocol ZIN-130-1504  
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Table 8 Clinical Laboratory Tests 
Hematology 
Clinical Chemistry 
Complete Blood Count 
(including): 
Red blood cell (RBC) count 
White blood cell (WBC) count 
Hematocrit 
Hemoglobin 
Neutrophils* 
Lymphocytes* 
Monocytes* 
Basophils* 
Eosinophils* 
Platelet count 
(estimate not acceptable) 
 
 
 
Blood urea nitrogen 
Alanine aminotransferase 
Aspartate aminotransferase  
Alkaline phosphatase 
Lactate dehydrogenase 
Gamma glutamyl transpeptidase 
 
Total protein 
Albumin 
Creatinine 
Glucose 
Phosphate 
Uric acid 
Pregnancy Test: 
Immunogenicity: 
Serum pregnancy test (at Screening 
and at Follow-up Visit)** 
Anti-HSP-130 
antibodies testing 
Serology: Screening only 
Serology (anti-HIVAb) 
Urinalysis: specific gravity, pH, protein, glucose, ketones, 
blood, leukocyte esterase, nitrite, bilirubin, urobilinogen, 
WBC, and RBC 
 
Spot urine for protein/creatinine ratio (PCR) 
*absolute counts and percentage 
** serum pregnancy test for all subjects except those who are postmenopausal for 5 years or have undergone 
surgical sterilization 
For subjects enrolled in Cycle 0, samples will be obtained for clinical chemistry at Screening, 
Days 3, 7, 11, 20, and at Follow-up Visit. For subjects enrolled Cycles 1 and 4, samples will 
be obtained for clinical chemistry at Screening and at Days 3, 6, 10, 11, 12, 20, and at the 
Follow-up Visit after Cycle 4 or upon subject discontinuation. In addition, samples will be 
collected for clinical chemistry on Days 3, 6, 10, 11, 12, and 20 in Cycles 2 and 3. 
For subjects in Cycle 0, samples will be obtained for hematology at Screening, Day 3, Day 7, 
Day 14, Day 20, and Follow-up Visit. For subjects in Cycles 1-4, samples will be obtained 
for hematology at Screening, and on Days 3, 6, 10, 11, 12, 15, 20, and at the Follow-up Visit 
after Cycle 4 or upon subject discontinuation. In addition, samples will be obtained for 
hematology on Days 3, 6, 10, 11, 12, 15, and 20 in Cycles 2 and 3. For subjects in Cycle 0, 
Cycles 1 and 4, samples will be obtained for urinalysis at Screening, and at Follow-up Visit.  
A certified central laboratory will be used to process and provide results for the clinical 
laboratory tests. The baseline laboratory test results for clinical assessment of a particular 
analyte will be defined as the last measurement prior to the initial dose of HSP-130. 
 
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Protocol ZIN-130-1504  
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The total blood volume drawn for clinical laboratory outlined above for all visits will be 
approximately 100 mL for subjects enrolled in Cycle 0 and 250 mL for subjects enrolled in 
Cycles 1-4, respectively. 
Sample collection, handling, and shipment instructions are provided in the Laboratory 
Manual supplied to the site. 
Additional laboratory tests will be obtained if clinically significant abnormalities are present 
on the previous evaluation. Clinically significant abnormalities observed after HSP-130 
administration are to be followed to resolution (i.e., become stable, return to baseline or are 
explainable). All abnormal laboratory results are to be coded for clinical significance per the 
judgment of the Investigator. 
Laboratory abnormalities will be considered as AEs only if they result in discontinuation 
from the study, necessitate therapeutic intervention, and/or if the Investigator considers them 
to be AEs. Grading of laboratory abnormalities will be according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (6). 
6.2.9 
HIVAb Testing 
Subjects will have blood tested by a certified laboratory for the presence of HIVAb at 
Screening. Only those subjects negative for the presence of antibodies will be allowed to 
enroll in the study. This exclusion is based on the fact that the current study is intended to 
assess the effect of HSP-130 in subjects undergoing myelosuppressive chemotherapy and 
response to treatment may be confounded in this setting. The results of the HIVAb testing 
will be retained by the study site under confidential restriction. 
6.2.10 
Anti-HSP-130 Antibody Testing 
Cycle 0: 
Blood samples for anti-HSP-130 antibody testing will be collected by venipuncture into 
7 mL evacuated collection tubes on Day 1 (prior to dose), on Day 14, and on Day 20. 
Cycle 1-4: 
Blood samples for anti-HSP-130 antibody testing will be collected by venipuncture into 
7 mL evacuated collection tubes on Day 2 (prior to HSP-130 dose) and on Day 20 in 
Cycles 1 and 4. 
Blood samples for antibody analysis will be collected - 7 mL of blood to provide 
approximately 3 mL serum. The serum will be split into 3 polypropylene cryovials (1 mL 
each). One cryovial will be used for the analysis and 2 cryovials will be retained as a backup. 
 
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Protocol ZIN-130-1504  
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6.2.11 
Pregnancy Test 
A pregnancy test will be performed for all subjects except those who are postmenopausal for 
5 years or have undergone surgical sterilization at Screening and at the Follow-up Visit after 
Cycle 0 and after Cycle 4. 
6.2.12 
Total Blood Volume to be Collected During the Study 
For subjects who enroll in Cycle 0 group the total blood volume sampled is approximately 
224 mL, which breaks down as follows: 
• 100 mL of blood collected for clinical laboratory assessments 
• 32.9 mL of blood collected for PD assessments 
• 70 mL of blood collected for PK analyses 
• 21 mL of blood collected for anti-HSP-130 antibody testing 
For subjects enroll in Cycles 1-4 group the total blood volume sampled is approximately 
456 mL, which breaks down as follows: 
• 250 mL of blood collected for clinical laboratory assessments 
• 37.8 mL of blood collected for PD assessments 
• 140 mL of blood collected for PK analyses 
• 28 mL of blood collected for anti-HSP-130 antibody testing 
Total blood volume for subjects will include an additional 10-15 mL taken for pregnancy 
testing. 
Any additional blood that may be taken is unlikely to cause the total volume of blood to 
exceed approximately 239 mL for Cycle 0 group and 471 mL for Cycles 1-4 group. 
6.3 
Study Procedures 
6.3.1 
Screening Visit (Day -14 to Day -1) 
Subjects will undergo Screening procedures within 14 days prior to HSP-130 administration.  
All Screening procedures will be completed prior to assignment to treatment. Subjects 
satisfying all inclusion/exclusion criteria may be enrolled in the study. 
6.3.2 
Dose Escalation Assessment 
The safety of administered HSP-130 will be assessed throughout the study and will include 
AEs, AEs of special interest, laboratory assessments, vital signs and physical examination. 
 
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Protocol ZIN-130-1504  
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Escalation to the next dose will be allowed based on the pre-specified safety evaluation 
within a minimum of 5 evaluable subjects. Appropriateness of escalation to the next dose 
will be based on assessment of vital signs, concomitant medications, laboratory assessments, 
and any AEs occurring post-dose administration through Day 20 of the HSP-130 dosing 
periods. If, there is no contraindication based on these assessments within 5 evaluable 
subjects, screening for the subsequent dose level can be initiated. 
Cycle 0 (3 mg to 6 mg): 
The ability to dose escalate will specifically include consideration of the following: 
1. Dose escalations will not occur under the following conditions: 
• If ≥ 3 subjects experience any of the following (based on the small study numbers 
[n = 6] upon which escalation decisions are made): 
• Each of these subjects experience the same serious adverse event (or SAE 
reflecting an analogous medical event), unless unrelated to the study drug. In 
addition, Hospira will assess aggregate SAE profiles of subjects and identify 
emerging patterns consistent with a potential unexpected causal drug event 
association.  
• Each of these subjects experiences severe lab abnormalities including 
• Transaminase elevations (ALT or AST) (e.g., > 5 times ULN) without 
underlying alternative explanation 
• Significant decreases in renal function from baseline (e.g., 50% decrease in 
eGFR) 
• Clinically significant leukocytosis (e.g., > 50 x 109/L) 
• Clinically significant thrombocytopenia (e.g., < 30 x 109/L) 
• Onset of clinically evident splenomegaly within the 30 day assessment period  
2. Additionally, concomitant medications will be assessed to see if there is 
any consistent altered pattern of medication use for treatment emergent SAEs.  If 
observed, this finding will be assessed for implications for dose escalation. 
3. If Adverse Events of Special Interest are reported as SAEs and are reported in 
disproportionate numbers than would be expected based on published safety profiles 
(United States Product Information [USPI] or Summary of Product Characteristics 
[SPC]) for approved pegfilgrastims, this will be assessed for implications for dose 
escalation. 
 
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Protocol ZIN-130-1504  
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Cycles 1-4 (6 mg to 12 mg): 
The ability to dose escalate will specifically include consideration of the following: 
1. Dose escalation to 12 mg will be not be considered until Hospira has analyzed the data 
from the previous Cycle 0 for 3 mg and 6 mg cohorts as well as the Cycles 1-4 for 6 mg 
cohort (and 3 mg cohort, if performed) and the data are submitted to the FDA for review.  
At this point, escalation to the 12 mg cohort may only proceed if the exposure pattern of 
the PK/PD responses suggests that higher doses are required and both Hospira and the 
FDA agree to proceed. 
2. If the decision is jointly made with the FDA to study a 12 mg dose, Hospira will stop 
patient enrollment in the 12 mg cohort with criteria jointly agreed upon during that 
review but will include criteria such as the following. 
 
Patient enrollment in the 12 mg cohort will be stopped if any of the following occur: 
a. If any patient experiences a grade 5 toxicity suspected to be related to HSP-130 
b. If ≥ 2 of the planned 12 subjects in the cohort experience any of the following: 
• Each of these subjects experiences the same serious adverse event (or SAE 
reflecting an analogous medical event), unless unrelated to the study drug.  In 
addition, Hospira will assess aggregate SAE profiles of subjects and identify 
emerging patterns consistent with a potential unexpected causal drug event 
association. 
• Each of these subjects experiences severe lab abnormalities including: 
• Transaminase elevations (ALT or AST) (e.g., > 5 times ULN) without 
underlying alternative explanation 
• Significant decreases in renal function from baseline (e.g., 50% decrease 
in eGFR) 
• Clinically significant leukocytosis (e.g., > 50 x 109/L) 
• Clinically significant thrombocytopenia (e.g., < 30 x 109/L) 
• Onset of clinically evident splenomegaly within the 30 day assessment 
period 
c. If ≥ 2 patients in the 12 mg cohort experience grade 3 or 4 known G-CSF-related 
toxicities as informed by the known safety profiles of approved pegylated or 
non-pegylated filgrastims. 
d. If Adverse Events of Special Interest are reported as SAEs and are reported in 
disproportionate numbers than would be expected based on published safety 
profiles (USPI or SPC) for approved pegfilgrastim. 
3. Additionally, concomitant medications will be assessed to see if there is 
any consistent altered pattern of medication use for treatment emergent SAEs.  If 
observed, this finding will be assessed for implications for dose escalation. 
4. If Adverse Events of Special Interest are reported as SAEs and are reported in 
disproportionate numbers than would be expected based on published safety profiles 
 
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Protocol ZIN-130-1504  
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(USPI or SPC) for approved pegfilgrastims, this will be assessed for implications for dose 
escalation. 
If subject safety would be compromised by further subject enrollment at a specific dose level 
(3 mg, 6 mg, or 12 mg) as determined by the Medical Monitor, further enrollment at that 
dose of HSP-130 may be terminated. 
6.3.3 
Follow-up Visit 
Cycle 0: 
Subjects will come for a Follow-up Visit 30 (± 2) days after HSP-130 administration in 
Cycle 0. After completion of Cycle 0, each of the subjects in these dosing groups will have 
completed their participation in assessment of HSP-130. The site will be offered 
reimbursement for treatment with EU-approved Neulasta in accordance with local standard 
of care by the Investigator with subsequent non-study chemotherapy regimen. 
Cycles 1-4: 
Subjects will come for a Follow-up Visit 30 (± 2) days after HSP-130 administration in 
Cycle 4, after which they will be considered to have completed the study. Any information 
related to treatment associated with an AE will also be collected at the time of Follow-up 
Visit. 
6.4 
Pharmacodynamic and Pharmacokinetic Evaluation 
6.4.1 
Collection of Samples for Analysis 
Sample collection, handling, and shipment instructions will be provided in the Laboratory 
Manual supplied to site. 
The total amount of blood required per subject for PD and PK analysis for subjects enroll in 
Cycle 0 is approximately 126 mL and for subjects enroll in Cycles 1-4 is approximately 
196 mL. 
Pharmacodynamic sampling 
Cycle 0 
Blood samples for ANC (2.7 mL) and CD34+ count (2.0 mL) will be collected by 
venipuncture into evacuated collection tubes within 1 hour prior to dose administration on 
Day 1 and at 48, 96, 144, 192, 240, and 312 hours post-dose. 
The total number of samples planned for PD analysis (ANC and CD34+ count) in Cycle 0 is 
7, resulting in approximately 32.9 mL of blood volume. 
 
 
 
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Protocol ZIN-130-1504  
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Cycles 1-4 
Blood samples for ANC (2.7 mL) will be collected by venipuncture into evacuated collection 
tubes within 1 hour prior to dose administration on Day 2 of the chemotherapy cycle and at 
48, 96, 144, 192, 240, and 312 hours post-dose. This sample collection schedule will be only 
applied to Cycles 1 and 4 with HSP-130 treatment groups. 
The total number of samples planned for PD analysis (ANC) in Cycles 1 and 4 is 14, 
resulting in approximately 37.8 mL of blood volume. 
Pharmacokinetic sampling 
Cycle 0 
Blood samples (7.0 mL) for HSP-130 assay will be collected by venipuncture into evacuated 
collection tubes within 1 hour prior to dose administration on Day 1 and at 6, 12, 24, 48, 96, 
144, 192, 240, and 312 hours post-dose. 
The total number of samples planned for HSP-130 assay in Cycle 0 is 10, resulting in 
approximately 70 mL of blood volume. 
Cycles 1-4 
Blood samples (7.0 mL) for HSP-130 assay will be collected by venipuncture into evacuated 
collection tubes within 1 hour prior to dose administration on Day 2 of the chemotherapy 
cycle and at 6, 12, 24, 48, 96, 144, 192, 240, and 312 hours post-dose. This sample collection 
schedule will be applied only to Cycles 1 and 4 with HSP-130 treatment groups. 
For PK analysis, 7 mL of blood will be collected at each sampling time point to provide 
approximately 3 mL serum. The serum will be split into 2 polypropylene cryovials (1.5 mL 
each). One cryovial will be used for the analysis and 1 cryovial will be retained as a backup. 
The timing of blood collections will take priority over all other scheduled study activities 
except for dosing. The time that each blood sample is collected will be recorded to the 
nearest minute. 
The total number of samples planned for HSP-130 assay in Cycles 1 and 4 is 20, resulting in 
approximately 140 mL of blood volume. 
6.4.2 
Pharmacodynamic Variables 
Cycle 0 
• 
Primary Variable: AUECANC 
• 
Secondary Variables: ANC_Emax, ANC Tmax, AUECCD34+, CD34+_Emax, 
CD34+ Tmax 
The PD variables will be calculated using non-compartmental methods. 
 
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Protocol ZIN-130-1504  
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Cycles 1-4 
• 
Primary Variable: DSN (defined as days with grade 4 neutropenia 
[ANC < 0.5 x 109/L]) in Cycle 1. 
• 
Secondary Variables: DSN in Cycle 4. ANC nadir concentration, Time of nadir 
concentration, AUEC, incidence of FN, defined as tympanic or axillary body 
temperature > 38.5°C for > 1 hour with ANC < 1.0 x 109/L, incidence of severe 
neutropenia (grade 4, ANC < 0.5 x 109/L) and time to ANC recovery (the first day 
with ANC ≥ 2.0 x 109/L after any day with ANC < 2.0 x 109/L) in Cycle 1 and 
Cycle 4. 
The PD variables will be calculated using non-compartmental methods. 
6.4.3 
Pharmacokinetic Variables 
Cycle 0 
• 
Primary Variables: AUC0-∞ and Cmax 
• 
Secondary Variables: AUC0-t, Tmax, t1/2, λz and CL 
The PK variables will be calculated using non-compartmental methods. 
Cycles 1-4 
• 
Primary Variables: AUC0-t, and Cmax 
• 
Secondary Variables: AUC0-∞, Tmax, t1/2, λz and CL 
The PK variables will be calculated using non-compartmental methods 
6.5 
Measurement Methods 
6.5.1 
Pharmacodynamic Assay 
Analysis of Samples: ANC will be determined at the central clinical laboratory conducting 
the clinical laboratory tests. CD34+ count will be determined by flow cytometric method. 
6.5.2 
Pharmacokinetic Assay 
Analysis of Serum Samples: Serum pegylated G-CSF concentrations will be determined from 
an aliquot of human serum using a validated enzyme-linked immunosorbent assay (ELISA) 
procedure with double-antibody sandwich method with quantitation by absorbance. This 
method is suitable for determination pegylated G-CSF in human serum over the range of 100 
to 5000 pg/mL. The method meets the requirements of the Guidance for Industry 
Bioanalytical Method Validation: (May 2001) of the FDA and a subsequent revision to the 
Guidance (September, 2013) (41), (42). 
 
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Protocol ZIN-130-1504  
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6.5.3 
Antibody Assay 
Samples for the assessment of anti-HSP-130 antibodies will be assayed in accordance with 
FDA Guidelines for immunogenicity testing (43), (44). 
A validated electrochemiluminescent (ECL) assay will be used to measure sera for the 
presence of anti-HSP-130 antibodies. Sera that are confirmed as positive will be tested in a 
cell-based assay for neutralizing antibodies (NAb) that neutralize the biologic activity of 
HSP-130. In parallel, serum samples will be assessed for anti-PEG binding antibodies using 
an independent assay both pre- and post-treatment. 
6.5.4 
Sample Analysis Repeats 
Analysis of samples that are considered suspect will be repeated according to the laboratory's 
operating procedures on sample repeats. A table of repeat values must be included in the 
analytical report with justification for the repeat analysis and the accepted value. 
6.6 
Subject Enrollment 
Only subjects satisfying the inclusion and exclusion criteria will be enrolled. Prior to 
administration of the HSP-130, subjects will be given unique numbers and sequentially 
assigned to 1 of the 3 treatment groups. 
6.7 
Subject Replacement 
A total of 24 to 36 patients will be enrolled initially depending on whether a second 3 mg 
cohort is required; a further 12 patients totaling approximately 36 to 48 patients will be 
treated if the 12 mg cohort is enrolled, as defined in Section 6.3.2. Subjects who withdraw 
prior to Cycle 2 may be replaced to support the full complement of subjects (minimum of 
8 evaluable subjects) for primary endpoint data generation for Cycle 1. 
 
 
 
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Protocol ZIN-130-1504  
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7 
WITHDRAWAL AND EARLY DISCONTINUATION  
7.1 
Early Discontinuation of the Study 
Hospira may discontinue this study prematurely in its entirety for reasonable cause provided 
that written notice is submitted at a reasonable time in advance of the intended termination. 
The Investigator may also discontinue the study at his/her site for reasonable cause after 
notifying the IRB/IEC and providing written notice to Hospira at a reasonable time in advance 
of the intended termination. Advanced notice is not required by either party if the study is stopped 
due to safety concerns. 
The study will be terminated by the Sponsor if either of the following occurs: 
• Lack of efficacy for 6 mg is demonstrated, i.e., more than 3 patients experience severe 
neutropenia for a duration of > 5 days, with severe neutropenia as < 0.5 x 109/L OR 
• If more than 3 patients in the 3 mg cohort or more than 3 patients in the 6 mg cohort 
experiences grade 3, 4, or 5 known G-CSF related toxicities informed by the known 
safety profiles of approved pegylated or non-pegylated filgrastims (19), (23) 
7.2 
Early Discontinuation of Individual Subjects 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time and for any reason without prejudice to his 
or her future medical care. 
Subjects may be discontinued or withdrawn from the study for a number of reasons, which 
must be recorded on the appropriate eCRF. 
A subject will be discontinued from this study if any of the following criteria are met: 
• Subject withdrawal of consent 
• Clinical presentation consistent with splenic rupture following study drug 
administration 
• Evidence of acute respiratory distress syndrome following study drug administration 
• Evidence of serious allergic reaction following study drug administration 
• At the discretion of the Principal Investigator or Medical Monitor, the subject 
presents with a new onset significant condition during study conduct that may 
influence the subject's welfare or study endpoints. 
• At the discretion of the Principal Investigator or Medical Monitor, the subject will be 
discontinued if deemed appropriate in the best interest of the subject's welfare. 
Withdrawal for any reason is considered to be a premature discontinuation. Following 
discontinuation from the study, the subject will be treated in accordance with the 
Investigator's best clinical judgment. Once a subject has prematurely discontinued from the 
 
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Protocol ZIN-130-1504  
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study, end of study assessments will be performed. For subjects who received HSP-130, all 
study assessments should be completed if possible, inclusive of potential serial blood 
collection in cases of identified positive anti-HSP-130 antibody results. 
Enrolled subjects who discontinue due to an AE will have events documented and will be 
followed to satisfactory resolution or until the Principal Investigator or sub-investigator 
deems the event to be chronic or not clinically significant or the subject to be stable. If 
clinically indicated, a complete laboratory evaluation (chemistry, hematology, urinalysis and 
spot urine for PCR) will be performed. 
The date and reason for a subject's premature discontinuation from the study will be recorded 
in the source document and entered in the appropriate section of the eCRF. 
 
 
 
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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
8 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
The Investigator will monitor each subject for clinical and laboratory evidence of AE on a 
routine basis throughout the study. The Investigator will assess and record any AE in detail 
including the date of onset, description, severity, time course, duration and outcome, 
relationship of the AE to HSP-130, an alternate etiology for events not considered related to 
HSP-130, final diagnosis, if known, and any action(s) taken. For AEs to be considered 
intermittent, the events must be of similar nature and severity. AEs, whether in response to a 
query, observed by site personnel, or reported spontaneously by the subject will be recorded. 
All Serious AEs will be followed to resolution or until the Principal Investigator or 
sub-investigator deems the event to be chronic or not clinically significant or the subject to 
be stable. 
8.1 
Definitions 
8.1.1 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not the event is considered 
causally related to the use of the investigational product. 
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well 
as from accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening 
of a pre-existing condition or illness is considered an AE. Clinically significant abnormalities 
are to be followed to resolution (i.e. become stable, return to normal, return to baseline, or 
become explainable). 
Laboratory abnormalities and changes in vital signs are considered to be AEs only if they 
result in discontinuation from the study, necessitate therapeutic medical intervention, meet 
protocol-specific criteria, and/or if the Investigator considers them to be AEs. 
An elective surgery/procedure scheduled to occur during the study will not be considered an 
AE if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been planned prior to study entry, including kidney transplants. 
However, if the pre-existing condition deteriorates unexpectedly during the study  
(i.e., surgery performed earlier than planned), then the deterioration of the condition for 
which the elective surgery/procedure is being done will be considered an AE. 
8.1.2 
Adverse Events of Special Interest 
The following events are considered AEs of Special Interest for HSP-130. See Section 
10.2.5.1 for definitions and clarification. 
1. Potential Allergic Reactions 
 
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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
2. Splenomegaly 
3. Splenic rupture 
4. Acute Respiratory Distress Syndrome 
5. Alveolar Hemorrhage  
6. Hemoptysis 
7. Leukocytosis 
8. Thrombocytopenia 
9. Capillary Leak Syndrome 
10. Cytokine Release Syndrome 
11. Cutaneous Vasculitis 
8.1.3 
Serious Adverse Events 
If an AE meets any of the following criteria, it is to be reported to Hospira as a SAE within 
24 hours of occurrence or notification of the study site: 
Death of Subject 
An event that results in the death of a subject. 
Life-Threatening 
An event that, in the opinion of the investigator, would have resulted 
in immediate fatality if medical intervention had not been taken. 
This does not include an event that would have been fatal if it had 
occurred in a more severe form. 
Hospitalization 
An event that results in an admission to the hospital for any length 
of time. This does not include an emergency room visit or admission 
to an out-patient facility. 
Prolongation of 
Hospitalization 
An event that occurs while the study subject is hospitalized and 
prolongs the subject's hospital stay. 
Congenital 
Anomaly 
An anomaly detected at or after birth or any anomaly that result in 
fetal loss. 
Persistent or 
Significant 
Disability/ 
Incapacity 
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject. Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle). 
 
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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Important 
Medical Event 
Requiring 
Medical or 
Surgical 
Intervention to 
Prevent Serious 
Outcome 
 
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity). Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Other 
Both spontaneous and elective abortions are to be treated as SAEs. 
A list of AEs that must always be reported as SAEs during this study is provided in 
Appendix E. 
8.1.4 
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a suspected adverse reaction 
that is both serious and unexpected. Investigators will be notified of SUSARs in a manner 
and timeframe consistent with applicable national regulatory requirements. 
The study will comply with all local regulatory requirements. This study adheres to the 
definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting. 
8.2 
Adverse Event Severity 
The Investigator will use the following definitions to rate the severity of each AE: 
Mild 
The event is transient and easily tolerated by the subject. 
Moderate 
The event causes the subject discomfort and interrupts the subject's 
usual activities. 
Severe 
The event causes considerable interference with the subject's usual 
activities and may be incapacitating or life-threatening. 
 
8.3 
Causality of Adverse Events 
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as related and 
unrelated, as appropriate, and report such an assessment in accordance with the SAE 
reporting requirements if applicable. 
• An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE; 
 
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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
A subject experiencing 1 or more SAEs will receive treatment and Follow-up evaluations by 
the Principal Investigator or may be referred to another appropriate physician for treatment 
and Follow-up. 
8.6 
Pregnancy 
Hospira must be notified immediately if a female study subject becomes pregnant during the 
study. The Investigator must report the pregnancy by telephone to the Safety Medical 
Monitor listed in Section 8.5. The Investigator must also complete and send the Clinical Trial 
Pregnancy Report Form within 5 working days of initial sponsor notification. The 
Investigator will follow the course of the subject’s pregnancy and submit reports to Hospira 
on the health of the subject and fetus at least each trimester, at birth, and once after delivery, 
within 3 to 6 months. 
Pregnancy in a study patient is not considered an AE or SAE. Study subjects who become 
pregnant will be discontinued from the study. The medical outcome of an elective or a 
spontaneous abortion in a female study subject is considered an SAE, and must be reported to 
Hospira within 24 hours of learning of the event, as noted in Section 8.5. 
Adequate methods of contraception to prevent pregnancy are to be maintained throughout the 
course of the study in study subjects as defined by the protocol. 
 
 
 
Page 78 of 145 
 


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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
10 STATISTICAL CONSIDERATIONS 
The sections below summarize the intended statistical methods and analyses for the study. A 
more detailed statistical analysis plan (SAP) will be written prior to finalization of the 
clinical trial database. Any changes to the planned methods and analyses will be described 
and justified in the protocol and/or in the final clinical study report, as appropriate. 
10.1 Statistical Methods 
The SAP describing in detail the statistical analysis methods used will be prepared and 
finalized prior to study database lock. 
For continuous variables, number of observations (N), mean, median, standard deviation 
(SD), minimum and maximum will be presented. For categorical variables, N and percent 
will be shown. 
10.1.1 
Subject Population/Data Sets to be Evaluated 
Safety and PK analyses will be based on the actual treatment each subject received. PD 
analysis will be based on assigned treatment. Any subject receiving treatment other than that 
of the assigned Treatment Group will be listed in the clinical study report. 
Safety Population: 
All subjects who receive at least 1 dose of HSP-130 will be included in the Safety 
Population. All safety analyses will be conducted on the Safety Population. 
Full Analysis Set (FAS): 
All subjects who receive at least one does of HSP-130 are included in FAS. In analysis of a 
particular parameter for a particular cycle(s), only those subjects who have sufficient data in 
the cycle(s) to calculate the parameter will be included. Sufficient data is defined as having 
more than 3 measurable values where the parameter can be reliably calculated. Subjects who 
have confirmed positive anti-HSP-130 antibody results will not be included. 
10.1.2 
Sample Size Determination 
No formal sample size calculation was conducted. 
10.1.3 
Data and Interim Analyses 
There will be no interim analyses performed in this study. 
10.1.4 
Handling of Missing Data 
Missing data will not be imputed. All subjects in FAS with available data will be included in 
summaries of each PK/PD parameter or concentration time point. All subjects’ data will be 
listed. 
 
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Protocol ZIN-130-1504  
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10.2 Statistical Analyses 
10.2.1 
Subject Disposition and Demography 
The number of subjects enrolled and the reason for discontinuation from the study will be 
summarized by treatment. 
The demographics and the medical history will be summarized. 
10.2.2 
Assessment of Efficacy 
Efficacy parameters will be summarized by treatment. Individual subject’s efficacy data will 
be listed. 
10.2.3 
Assessment of Pharmacodynamics and Pharmacokinetics 
Pharmacodynamic Assessment 
The primary PD parameters of AUECANC results from Cycle 0 and DSN results from Cycle 1 
will be assessed to determine appropriate doses for Phase 3 studies. Additional PD results 
may be assessed as appropriate. 
Cycle 0: 
Pharmacodynamic parameters of AUECANC, ANC_Emax, ANC Tmax, AUECCD34+, 
CD34+_Emax, and CD34+ Tmax will be calculated for assessment. 
If the PD response (AUECANC and/or AUECCD34+) of 3 mg HSP-130 and 6 mg HSP-130 in 
Cycle 0 indicate that the 3 mg dose level is sub-therapeutic, the 3 mg dose level will not be 
included in Cycles 1-4 assessment. This design feature will ensure that no subject with 
chemotherapy will be treated with sub-therapeutic dose of HSP-130. Additional PD results 
may be assessed as appropriate. 
Cycles 1-4: 
Pharmacodynamic parameters of DSN (defined as days with grade 4 neutropenia 
[ANC < 0.5 x 109/L]) in Cycle 1, DSN in Cycle 4, ANC nadir concentration, time of nadir 
concentration, area under the effect curve (AUEC), incidence of febrile neutropenia, defined 
as tympanic or axillary body temperature > 38.5°C for > 1 hour and ANC < 1.0 x 109/L, 
incidence of severe neutropenia (grade 4, ANC < 0.5 x 109/L) and time to ANC recovery (the 
first day with ANC ≥ 2.0 x 109/L after any day with ANC < 2.0 x 109/L) in Cycle 1 and 
Cycle 4 will be calculated for assessment. 
Descriptive statistics including number of observations (N), mean, SD and associated 
coefficient of variation (CV), minimum and maximum for each PD parameter by treatment 
will be reported. 
 
 
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Protocol ZIN-130-1504  
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Pharmacokinetic Assessment 
Cycle 0: 
Pharmacokinetic parameters of AUC0-∞, Cmax, AUC0-t, Tmax, t1/2, λz, and CL will be 
calculated for assessment. 
Cycles 1-4: 
Pharmacokinetic parameters of AUC0-t, Cmax, AUC0-∞, Tmax, t1/2, λz, and CL will be 
calculated for assessment. 
Descriptive statistics including N, mean, SD, minimum and maximum for each PK parameter 
by treatment will be reported. 
10.2.4 
Additional Assessments 
Data collected in with WHO Performance Status, CISNE, and FACT-N, will be summarized 
by treatment and listed for individual subjects. Descriptive statistics including N, mean, SD, 
minimum and maximum for numerical data, and counts and frequency for categorical data, 
will be presented. 
10.2.5 
Assessment of Safety 
Treatment emergent adverse events (TEAEs) will be summarized by system organ class and 
preferred terms (PT). Descriptive statistics including N, mean, SD, minimum and maximum 
for numerical data, and counts and frequency for categorical data, will be tabulated for 
laboratory tests, and vital signs by treatment group. Grading of laboratory abnormalities will 
be according to the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03 (6). 
10.2.5.1 
Adverse Events 
The Medical Dictionary for Drug Regulatory Activities (MedDRA) will be used to map AE 
descriptions to preferred terms (PT) and system organ classes. MedDRA version 17.1 or later 
will be used. 
AEs of Special Interest will be identified prospectively based on the safety information of the 
Neulasta, as described in the Neulasta (Amgen) Package Insert, and grouped by similar 
medical constructs. The AEs of Special Interest are further informed based on the known 
extension of the pharmacology of the drug as manifested by known clinical adverse reactions 
with G-CSFs. 
The following events are considered AEs of Special Interest for HSP-130 and will be 
summarized by the medical concept (narrow standard MedDRA queries [SMQ] and PT as 
appropriate): 
1. Potential Allergic Reactions  
 
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2. Splenomegaly 
3. Splenic rupture 
4. Acute Respiratory Distress Syndrome 
5. Alveolar Hemorrhage  
6. Hemoptysis 
7. Leukocytosis 
8. Thrombocytopenia 
9. Capillary Leak Syndrome 
10. Cytokine Release Syndrome 
11. Cutaneous Vasculitis 
Definitions of Adverse Events of Special Interest 
MedDRA version 17.1 or later is employed in this study to code event terms. Adverse Events 
of Special Interest are defined in the Statistical Analysis Plan. The Adverse Events of Special 
Interest were identified based on the safety profile of the originator product in accordance 
with the US prescribing information for approved US-approved G-CSFs (pegfilgrastim and 
filgrastim, Neulasta and Neupogen, respectively) and any potential preclinical or clinical 
Nivestim (EU-approved Hospira filgrastim) data that may inform the safety characterization 
for HSP-130. 
The methodology employed to medically group together similar medical constructs within 
MedDRA was as follows: where a SMQ in MedDRA 17.1 or later exists to summarize the 
adverse event of interest, the SMQ was employed to medically group together the PTs. In 
order to ensure adequate specificity, the SMQ narrow in MedDRA 17.1 or later was 
employed to offer a sensitive, but adequately specific approach to summarizing the adverse 
event of special interest. If an SMQ was not available in MedDRA 17.1 or later to summarize 
the adverse event of interest, a selection of PTs was identified by the sponsor to provide a 
medically comprehensive grouping of the medical concept.  
 
An AE will be considered to be treatment-emergent if the event started or worsened in 
severity after the HSP-130 administration up to and including 30 days post HSP-130 
administration. For TEAEs, the number and percentage of subjects who reported each PT 
will be summarized by treatment groups. Category of severity (mild, moderate, severe) and 
relationship to HSP-130 (related, not related) will be summarized by treatment group for 
TEAEs. Adverse events missing an indicated relationship to HSP-130 will be considered 
related to HSP-130. 
SAEs will be summarized by each treatment group and listed by each subject. 
 
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10.2.5.2 
Concomitant Therapy 
Concomitant therapies will be coded to their generic name using the latest version of World 
Health Organization (WHO) drug dictionary. Medications will be listed according to 
treatment group. The number of subjects taking medication prior to HSP-130 dosing and 
concomitant therapies taken after HSP-130 dosing will be tabulated by treatment group. 
10.2.5.3 
Vital Signs 
Baseline is defined as the last non-missing measurement prior to the start of HSP-130. 
Descriptive statistics will be applied to summarize blood pressure, heart rate, and temperature 
for each treatment group. 
10.2.5.4 
Clinical Laboratory Measurements 
All laboratory values outside the normal range will be flagged in the data listing. 
10.2.5.5 
Physical Examination, Chest X-ray, and ECG 
Physical examination data recorded at Screening and at Follow-up Visit (Day 30) after 
HSP-130 administration in Cycle 4 will be listed. Chest X-ray and ECG data will be listed. 
10.2.5.6 
Antibody Assay 
Antibody data will be listed. 
10.2.6 
Deaths 
Deaths will be summarized by each treatment group and listed by each subject. 
 
 
 
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11 REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS 
11.1 Declaration of Helsinki 
The Investigator and all parties involved in this study should conduct the study in adherence 
to the ethical principles based on the Declaration of Helsinki (See Appendix D), GCP, ICH 
Guidelines and the applicable laws and regulations. 
11.2 Good Clinical Practice 
The study will be conducted in accordance with SOPs that meet the current regulatory 
requirements and guidelines laid down by the ICH GCP in clinical studies and all applicable 
local regulatory requirements and laws. 
11.3 Ethical Approval 
11.3.1 
Initial Approval 
Prior to the release of HSP-130 for administration and the enrollment of subjects, IRB/IEC 
written approval of the following must be obtained: the conduct of the study at named site(s), 
the protocol and any amendment(s), the subject information sheet and ICF, any other written 
information that will be provided to the subjects, any advertisements that will be used and 
any subject compensation. 
11.3.2 
Approval of Amendments 
Proposed amendments to the protocol and aforementioned documents must be submitted to 
Hospira for review and submitted to the IRB/IEC for approval as applicable. Amendments 
requiring regulatory authority and/or IRB/IEC approval may be implemented only after a 
copy of the necessary approval letter(s) has been transmitted to Hospira. 
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented prior to receiving Hospira and/or IRB/IEC approval. However, in this case, 
approval must be obtained as soon as possible after implementation. 
11.3.3 
End of Trial Notifications 
The appropriate regulatory authorities and IRB/IECs will be informed about the end of the 
trial within the required timelines. 
11.4 Regulatory Authority Approval 
The study will be performed in compliance with applicable regulatory requirements. Clinical 
trial authorization from the appropriate regulatory authority must be obtained prior to the 
start of the study. In addition, the applicable regulatory authorities must approve amendments 
(as instructed by Hospira), receive suspected unexpected serious adverse reactions (SUSAR) 
reports and annual safety reports, when applicable, and be notified of the end of the trial. 
 
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11.5 Other Required Approvals 
In addition to IRB/IEC and regulatory approval, all other required approvals (e.g. approval 
from local Research and Development Board or Scientific Committee) will be obtained prior 
to recruitment of subjects into the study and shipment of the HSP-130. 
11.6 Insurance 
Hospira has civil liability insurance, which covers this study in all applicable countries. 
11.7 Pre-study Documentation Requirements 
The requirements and guidelines for authorization to ship HSP-130, as outlined in the 
applicable Hospira (and/or designee) SOPs, will be met prior to the release and use of the 
HSP-130, to include the collection of the essential documents outlined in ICH E6, Section 
8.2, which are required prior to the start of the study (See Appendix B). 
11.8 Informed Consent 
It is the Investigator’s responsibility to obtain a signed ICF from the subject after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the study, and 
before any study procedures are commenced. As detailed in Section 6.1, the subject should 
be given a copy of the approved subject information sheet and informed consent in their 
native language. The original copy of the signed and dated ICF must be retained in the 
clinic’s records, and is subject to inspection by representatives of Hospira, and/or 
representatives from regulatory authorities. (See Appendix C) 
11.9 Contact with General Practitioner 
It is the Investigator’s responsibility to inform the subject’s General Practitioner (where 
applicable) by letter that the subject is taking part in the study, provided the subject agrees to 
this and information to this effect is included in the subject information sheet and informed 
consent. A copy of this letter will be filed in the Investigator Site File. 
11.10 Subject Confidentiality 
The Investigator must ensure that the subject’s privacy is maintained. On the eCRF or other 
documents submitted to Hospira, subjects will be identified by a screening and/or enrollment 
number only. Documents that are not submitted to Hospira (e.g., signed informed consent) 
should be kept in a strictly confidential file by the Investigator. 
The Investigator shall permit direct access to subject’s records and source documents for the 
purposes of monitoring, auditing, or inspection by Hospira, authorized representatives of 
Hospira, regulatory authorities and IRB/IECs only. 
 
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11.11 Data Protection 
All personnel involved in the study will observe or work within the confines of applicable 
local data protection regulations. 
11.12 Study Documentation and Data Storage 
The Investigator must retain a comprehensive and centralized filing system of all 
study-related documentation for inspection by Hospira and representatives of regulatory 
authorities for at least 2 years after the last approval of a marketing application in an ICH 
region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of HSP-130. It is the responsibility of Hospira to inform the Investigator when 
these documents no longer need to be retained. 
A subject screening/enrollment log is to be completed at each investigative site. Data 
recorded on the screening/enrollment log are to include a subject identifier, the date of 
screening, and the reason the subject was not entered (if applicable). All subjects initially 
screened are to be recorded in this log. 
Documents will be stored in such a way that they can be easily accessed/data retrieved at a 
later date. Consideration should be given to security and environmental risks. Should the 
Investigator wish to assign the study records to another party or move them to another 
location, written agreement must be obtained from Hospira prior to the transfer. 
11.13 Disclosure of Information 
Information concerning the study, patent applications, processes, scientific data or other 
pertinent information is confidential and remains the property of Hospira. The Investigator 
may use this information for the purposes of the study only. 
The Investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study. This list will be maintained at the site, and will not be retrieved by 
Hospira or its designee. 
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by Hospira in connection with the development of HSP-130.  
This information may be disclosed as deemed necessary by Hospira to other clinical 
investigators, other pharmaceutical companies, to the FDA and to other governmental 
agencies. In addition, the information collected during this study may be added to research 
databases and used in the future by the Sponsor and its affiliated companies to study better 
measures of safety and effectiveness, study other therapies for subjects, develop a better 
understanding of disease(s) included in the study, or improve the efficiency, design and study 
methods of future clinical trials. To allow for the use of the information derived from this 
clinical study and to ensure complete and thorough analysis, the Investigator is obligated to 
provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC 
review, and regulatory inspection. 
 
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It is understood by the Investigator that Hospira will use information developed in this 
clinical study in connection with the development of HSP-130 and therefore may disclose it 
as required to other clinical investigators and to regulatory authorities. In order to allow the 
use of the information derived from this clinical study, the Investigator understands that 
he/she has an obligation to provide complete test results and all data developed during this 
study to Hospira. 
Verbal or written discussion of results prior to study completion and full reporting should 
only be undertaken with written consent from Hospira. 
11.14 Publication 
Hospira intends to publish the results of the study as a whole once all subjects have 
completed the study and the study has been analyzed. The Investigator may not publish the 
results until the study has been submitted for publication and must have prior written 
permission from Hospira. 
The Investigator or Hospira may not submit for publication or present the results of this study 
without allowing each of the other parties 30 days in which to review and comment on the 
pre-publication manuscript. 
The Investigator may not submit the results of the study for publication without the prior 
written consent of Hospira. 
 
 
 
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12 ADMINISTRATIVE OBLIGATIONS 
12.1 Source Data Access 
The Investigator/institution will permit study-related monitoring, audits/inspections, IRB/IEC 
review and regulatory inspection providing direct access to source documents. 
12.2 Language 
Electronic CRFs will be in English.  Generic names for concomitant therapies should be 
recorded in the eCRF wherever possible. 
All written material to be used by subjects must use vocabulary that is clearly understood, 
and be in the language appropriate for the study site. 
12.3 Data Collection 
Subject data will be collected in this study using an Electronic Data Capture (EDC) system. 
Hospira, or its designee, will supply to the site personnel access to the eCRFs. These forms 
will be used to transmit information collected during the study to Hospira or its designee and 
regulatory authorities, as applicable. The Investigator may formally designate authority to 
complete eCRFs to qualified staff by completing the signature log and requesting access 
rights to the EDC system for the designee. Every user of the system will be made aware of 
the fact that user name and password should never be shared and their electronic signature 
constitutes the legally binding equivalent of a hand-written signature. 
Electronic CRFs must be completed for each enrolled subject who signs the informed 
consent document for the study. Screening study data will be collected on the eCRF for all 
subjects. The system automatically records all changes in an electronic audit trail and 
requires a “reason for change” to be picked from a pre-defined list. If the reason for the 
correction is not obvious, a brief explanation (e.g. transcription error) should accompany the 
change. All information recorded on the eCRFs forms must reflect the information in the 
subject source documents. 
For screen failed subjects, the Investigator or designee will capture in source the subject’s 
demographic data, data collected from all completed screening procedures, and reason for 
screen failure. Only the subject’s demographic data, informed consent, reason for screen 
failure and SAEs will be entered in the EDC. 
The Investigator will review the eCRFs for completeness and accuracy and electronically 
sign each set of eCRFs. Hospira personnel (or their representatives) will periodically review 
the eCRFs for completeness and accuracy. Hospira personnel (or their representatives) will 
be allowed access to all source documents in order to verify eCRF entries. 
 
 
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12.4 Monitoring 
It is understood that monitors from Hospira (and/or their designee), and any authorized 
personnel contracted to Hospira, may contact and visit the Investigator, and that they will be 
allowed to inspect the various records of the study on request (eCRFs, source documents and 
any other related data), provided that subject confidentiality is maintained, and that the 
inspection is conducted in accordance with local regulations. 
It is the monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol, completeness, accuracy, consistency of the data, 
and adherence to regulatory requirements and ICH GCP guidelines. 
The Investigator agrees to co-operate with the monitor to ensure that any issues detected 
during the course of these monitoring visits will be resolved in a timely manner. 
12.5 Independent Data Monitoring Committee 
An independent data monitoring committee will not be utilized in this study. 
12.6 Quality Control and Quality Assurance 
Quality Control will be performed according to applicable SOPs. The study may be audited 
by Quality Assurance representative(s) of Hospira (or their designee). All necessary related 
data and documents will be made available for inspection. 
 
 
 
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34. Mayordomo JI, Lopez A, Vinolas N, Castellanos J, Pernas S, Domingo Alonso J, et al. 
Retrospective cost analysis of management of febrile neutropenia in cancer patients in Spain. 
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35. Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, et al. The 
Multinational Association for Supportive Care in Cancer risk index: A multinational scoring 
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of Supportive Care in Cancer. 2013;21(5):1487-95. 
37. Talcott JA, Finberg R, Mayer RJ, Goldman L. The medical course of cancer patients with 
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38. Klastersky J, Paesmans M, Georgala A, Muanza F, Plehiers B, Dubreucq L, et al. 
Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for 
complications. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2006;24(25):4129-34. 
39. Wagner LI, Beaumont JL, Ding B, Malin J, Peterman A, Calhoun E, et al. Measuring 
health-related quality of life and neutropenia-specific concerns among older adults 
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Neutropenia (FACT-N). Supportive care in cancer : official journal of the Multinational 
Association of Supportive Care in Cancer. 2008;16(1):47-56. 
40. Questionnaries. FACIT.org [Online]. [cited 2015 Apr 16]. Available 
at http://www.facit.org/FACITOrg/Questionnaires. Accessed on 23 Nov 2015. 
41. FDA CDER, Guidance for Industry: Bioanalytical Method Validation, May 2001. 
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42. FDA CDER, Guidance for Industry; Bioanalytical Method Validation Draft Guidance 
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43. FDA Draft Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein 
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14 APPENDICES 
 
 
 
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Appendix A. 
Responsibilities of the Clinical Investigator 
Clinical research studies Sponsored by Hospira are subject to the regulations of the US FDA.  
The responsibilities imposed upon Investigators by the FDA are summarized in the 
"Statement of Investigator" (Form FDA 1572), which is a form letter addressed to the 
Sponsor (Hospira), summarizing the Investigator's qualifications for the study and his/her 
willingness to follow FDA regulations with respect to the study. 
In signing a Form FDA 1572, the Investigator agrees to assume the following 
responsibilities: 
1. To conduct the study(ies) in accordance with the relevant, current protocol(s) and only 
make changes in a protocol after notifying Hospira, except when necessary to protect the 
safety, rights, or welfare of subjects. 
2. To personally conduct or supervise the described investigation(s). 
3. To inform any subjects, or any persons used as controls, that the drugs are being used for 
investigational purposes and to ensure that the requirements relating to obtaining 
informed consent in 21 CFR Part 50 and IEC/IRB review and approval in 21 CFR Part 56 
are met. 
4. To report to Hospira adverse experiences that occurs in the course of the investigation(s) 
in accordance with 21 CFR 312.64. 
5. To read and understand the information in the Investigator's Brochure, including the 
potential risks and side effects of the drug. 
6. To ensure that all associates, colleagues, and employees assisting in the conduct of the 
study(ies) are informed about their obligations in meeting the above commitments. 
7. To maintain adequate and accurate records of the conduct of the study and make those 
records available for inspection by representatives of Hospira, the IEC/IRB, and/or the 
appropriate regulatory agency, and to retain all study-related documents until notification 
from Hospira. 
8. To ensure that an IEC/IRB that complies with the requirements of 21 CFR Part 56 will be 
responsible for the initial and continuing review and approval of the clinical 
investigation. 
9. To promptly report to the IEC/IRB all changes in the research activity and all 
unanticipated problems involving risks to human subjects or others (including submission 
of any Expedited Safety Reports received from Hospira to the IEC/IRB), and to make no 
changes in the research without IEC/IRB approval, except where necessary to eliminate 
apparent immediate hazards to human subjects. 
10. To comply with all other requirements regarding the obligations of clinical Investigators 
and all other pertinent requirements in 21 CFR Part 312. 
 
 
 
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Appendix B. 
Documents Required Prior to Initiation of the Study 
As Sponsor of a clinical study, Hospira has an obligation to ensure that the study will be 
conducted by a qualified Investigator with sufficient resources (of time, personnel, and 
physical facilities) to conduct the study and to ensure that the Investigator understands and 
agrees to comply with applicable regulations, policies, and procedures. Prior to the beginning 
of any clinical study, the Investigator will be asked to provide the following documentation. 
1. A signed and dated protocol for the study. 
2. A signed and dated Form FDA 1572 certifying the Investigator's agreement to comply 
with the appropriate regulations governing the conduct of the study. 
3. A current curriculum vitae of the Investigator. If sub-investigators will participate in the 
study, curriculum vitae for each. 
4. A current medical license for the Investigator and each sub-investigator. 
5. Requirements for the IEC/IRB. 
6. A copy of the signed and dated letter of approval of the IEC/IRB. The letter must specify 
that both the protocol and ICF were approved (unless separate documentation that the 
informed consent was approved is provided). The letter must also specify the version 
number and/or date of the approved ICF. 
7. A dated list containing the names and affiliations of the members of the IEC/IRB, or the 
institution's General Assurance Number. 
8. If the Investigator and/or sub-investigator are a member of the IEC/IRB, a letter stating 
that he/she did not participate in the review or approval of the protocol or ICF. 
9. A model copy of the IEC/IRB-approved informed consent document to be used in the 
study. 
10. Dated, documented approval/favorable opinion of IRB of an Advertisement for patient 
recruitment. 
11. A list of reference ranges of values for all laboratory tests specified by the protocol for all 
laboratories utilized. 
12. A copy of the laboratory(ies) certification(s) or the authorization number of the 
certification(s), the name of the certifying authority, and the period of certification. 
13. A copy of the lab director’s curriculum vitae and current medical license. 
Financial Disclosure forms must be completed by each Investigator and all sub-investigators 
identified on the Form FDA 1572.  A Financial Disclosure, EU consent, is required to be 
completed for each Investigator and/or sub-investigator who is a resident of the European 
Union. 
 
 
 
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Appendix C. 
Elements of the Informed Consent Form 
Hospira requires that all informed consent and assent statements used in studies comply with 
FDA 21 CFR 50 (Protection of Human Subjects) and the ICH GCP Consolidated Guidance. 
To ensure compliance, the required elements of informed consent are listed below to aid the 
investigator in drafting an acceptable informed consent. Hospira will review a proposed 
informed consent prior to its submission to the IRB/IEC; alternatively, Hospira will supply to 
the Investigator a draft informed consent statement that may be submitted to the review 
committee. 
Signed informed consent will be obtained from all subjects participating in this study, or 
from the subject’s legally authorized representatives.  This informed consent must include 
the following items: 
1. A statement that the study involves research. 
2. An explanation of the purposes of the research. 
3. The approximate number of subjects involved in the trial. 
4. The expected duration of the subject’s participation. 
5. The trial treatment(s) and the probability for random assignment to each treatment. 
6. Identification of experimental procedures. 
7. The trial procedures to be followed, including all invasive procedures. 
8. The subject’s responsibilities. 
9. A description of any reasonably foreseeable risks or inconveniences to the subject and, if 
applicable, to an embryo, fetus, or nursing infant. 
10. A statement that the study may involve risks which are currently unforeseeable. 
11. The anticipated expenses, if any, to the subject for participating in the trial. 
12. A description of the reasonable expected benefits.  If there is no intended clinical benefit 
to the subject, this should be stated. 
13. The anticipated prorated payment, if any, to the subject for participating in the trial. 
14. The alternative procedure(s) or course(s) of treatment that may be available to the 
subject, and their important potential benefits and risks. 
15. A statement that the subject or the subject’s legally authorized representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial. 
16. An explanation as to whether any compensation or medical treatments are available if 
injury occurs.  If so, what the compensation consists of and/or where further information 
may be obtained. 
17. Whom to contact about information regarding the trial. 
18. Whom to contact about research subject’s rights (ideally not the investigator). 
19. Whom to contact in the event of trial-related injury of the subject. 
20. A statement that the monitor(s), auditor(s), the IRB/EC, and regulatory authorities (e.g., 
FDA) will be granted direct access to the subjects’ original medical records for 
verification of clinical trial procedures and/or data, without violating the confidentiality 
of the subject, to the extent permitted by the applicable laws and regulations and that, by 
signing a written ICF, the subject or the subject’s legally authorized representative is 
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21. Information regarding safeguards to be used against disclosure of subject information to 
non-clinical research-related personnel. 
22. A statement that the records identifying the subject will be kept confidential and, to the 
extent permitted by the applicable laws and/or regulations, will not be made publicly 
available.  If the results of the trial are published, the subject’s identity will remain 
confidential. 
23. The foreseeable circumstances and/or reasons under which the subjects’ participation in 
the trial may be terminated. 
24. Procedures for orderly termination of participation. 
25. A statement that participation is voluntary. 
26. A statement that refusal to participate will involve no penalty or loss of benefits. 
27. A statement that the subject may discontinue participation at any time without penalty or 
loss of benefits. 
28. A statement that a signed and dated copy of the informed consent is given to the subject. 
29. The statement, “I agree to participate...” 
30. A place for the subject or the subject’s legally authorized representative to print their 
name, sign and date. 
31. A place for the person who conducted the informed consent discussion to print their 
name, sign and date. 
32. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as www.ClinicalTrials.gov. 
 
 
 
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Appendix D. 
Declaration of Helsinki 
World Medical Association (WMA) Declaration of Helsinki- Ethical Principles for Medical 
Research Involving Human Subjects. Adopted by the 18th WMA General Assembly, 
Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on Paragraph 29 
added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION 
1. The WMA has developed the Declaration of Helsinki as a statement of ethical principles 
for medical research involving human subjects, including research on identifiable human 
material and data.  The Declaration is intended to be read as a whole and each of its 
constituent paragraphs should not be applied without consideration of all other relevant 
paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages 
other participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research.  The physician's knowledge and conscience 
are dedicated to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health 
of my patient will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act in the patient's best interest when providing 
medical care." 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects.  Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments).  Even the best current 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and 
burdens. 
9. Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights.  Some research populations are particularly 
vulnerable and need special protection.  These include those who cannot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue influence. 
 
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10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards.  No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation.  The welfare of animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment. 
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol.  The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed.  The protocol should include information regarding funding, 
Sponsors, institutional affiliations, other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study.  The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as 
beneficial in the study or access to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins.  This committee must be 
independent of the researcher, the Sponsor and any other undue influence.  It must take 
into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.  The committee must have the right to monitor 
ongoing studies.  The researcher must provide monitoring information to the committee, 
especially information about any SAEs.  No change to the protocol may be made without 
consideration and approval by the committee. 
16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications.  Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional.  The responsibility for the protection of research 
subjects must always rest with the physician or other health care professional and never 
the research subjects, even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research. 
 
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18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison with foreseeable benefits to them and to other individuals 
or communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed.  Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, and any other relevant aspects of the 
study.  The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal.  Special attention 
should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information.  After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified 
individual must then seek the potential subject's freely-given informed consent, 
preferably in writing.  If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse.  There may be situations 
where consent would be impossible or impractical to obtain for such research or would 
pose a threat to the validity of the research.  In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress.  In such situations the informed consent should 
be sought by an appropriately qualified individual who is completely independent of this 
relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative.  These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended 
to promote the health of the population represented by the potential subject, the research 
 
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cannot instead be performed with competent persons, and the research entails only 
minimal risk and minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorized representative.  The potential subject's dissent 
should be respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population.  In such circumstances the physician should seek informed consent from the 
legally authorized representative.  If no such representative is available and if the 
research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them unable 
to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee.  Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research.  Authors have a duty to make publicly available the results of 
their research on human subjects and are accountable for the completeness and accuracy 
of their reports.  They should adhere to accepted guidelines for ethical reporting.  
Negative and inconclusive as well as positive results should be published or otherwise 
made publicly available.  Sources of funding, institutional affiliations and conflicts of 
interest should be declared in the publication.  Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following 
circumstances: 
- 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
- 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be subject to any risk of serious 
or irreversible harm.  Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
 
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34. The physician must fully inform the patient which aspects of the care are related to the 
research.  The refusal of a patient to participate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the patient 
or a legally authorized representative, may use an unproven intervention if in the physician's 
judgment it offers hope of saving life, re-establishing health or alleviating suffering.  Where 
possible, this intervention should be made the object of research, designed to evaluate its 
safety and efficacy.  In all cases, new information should be recorded and, where appropriate, 
made publicly available. 
 
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Appendix E. 
Adverse Events – Categorized as SAEs  
A: Abortion (non-elective); Acute respiratory (pulmonary) failure; Adrenal hemorrhage; 
Agranulocytosis; Anemia, aplastic; Anaphylaxis, anaphylactic shock; Anaphylactoid 
reaction; Aorto-oesophageal fistula, Aplastic bone marrow; Apnea (all ages); Asphyxia (all 
ages); Asystole; Attempted suicide; AV Block, third degree (aka, complete heart block) 
B: Acute blindness; Brain death 
C: Cardiac arrest/circulatory arrest/cardiorespiratory arrest; Cavernous sinus thrombosis; 
Cerebral edema; Cerebral vascular accident (stroke) includes hemorrhagic, thrombotic, 
embolic strokes to any region of the brain; Congenital anomalies (non-trivial); Coma (all 
types); Creutzfeldt-Jakob Disease 
D: Deafness, acute; Death (all types); Disseminated Intravascular Coagulation (DIC), 
Dysplasia; Deep vein thrombosis (DVT) 
E: Encephalomyelitis; Encephalopathy F: Fibrillation, ventricular; Fetal distress, demise 
G: Gangrene; Gastrointestinal obstruction; Gastrointestinal perforation; Gastrointestinal 
rupture; Genitourinary obstruction; Genitourinary tract rupture; Genitourinary tract 
perforation; Glaucoma 
H: Hemorrhage, neonatal; Hemorrhage, retroperitoneal; Hepatitis, infectious and non-
infectious; Hemopericardium; Hepatic encephalopathy;  Hepatic failure, necrosis; 
Hepatocellular damage, neonatal; Hepato-renal syndrome; Hyperpyrexia, Malignant 
(“Malignant Hyperthermia”) 
I: Intestinal ischemia, necrosis or death; Intrauterine death; Infarction (myocardial, 
pulmonary, etc.) 
L: Laryngeal edema; Leukemia; Liver failure; Leukoencephalopathy, reversible or posterior 
multifocal; Lymphoma 
M: Malignancy, primary occurrence. Excludes non-melanotic skin cancer; Malignant 
hypertension; Meningitis; MS aggravation or MS-like syndrome; Myelitis; 
Myeloproliferative disorder 
N: Neuroleptic Malignant Syndrome 
P: Pancytopenia; Pleural fibrosis; Pregnancy, ectopic; Pulmonary hypertension, primary; 
Pulmonary fibrosis; Pulmonary hemorrhage; Pulmonary edema (acute); Psychosis, acute 
onset 
Q: Quadriplegia 
 
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R: Red cell aplasia; Renal failure, acute; Respiratory Distress Syndrome (neonatal); 
Respiratory arrest; Respiratory depression, neonatal; Respiratory paralysis; Respiratory 
obstruction; Respiratory tract perforation; respiratory tract rupture; Retrobulbar neuritis; 
Retinopathies; Retroperitoneal Fibrosis; Reye’s syndrome 
S: Sagittal sinus thrombosis; Sepsis/Septicemia; Status asthmaticus; Status epilepticus; 
Stevens-Johnson Syndrome; Stillbirth; Sudden Infant Death Syndrome (SIDS) 
T: Thrombocytopenia with platelet count <50,000 (severe); Thrombosis (excluding 
superficial sites); Torsades De Pointes; Toxic Epidermal Necrolysis 
U: Uterine perforation 
V: Vascular occlusion 
W: Wallenberg Syndrome 
 
 
 
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Appendix F. 
Neulasta® (pegfilgrastim, Amgen) Summary of Product 
Characteristics  
Summary of Product Characteristics Updated May-2015| Amgen Ltd 
 
 
 
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NEULASTA
Summary of Product Characteristics Updated 24-Jun-2015 | Amgen Ltd
1. Name of the medicinal product
Neulasta 6 mg solution for injection.
2. Qualitative and quantitative composition
Each pre-filled syringe contains 6 mg of pegfilgrastim* in 0.6 ml solution for injection. The concentration is 10 mg/ml 
based on protein only**.
*Produced in Escherichia coli cells by recombinant DNA technology followed by conjugation with polyethylene glycol 
(PEG).
** The concentration is 20 mg/ml if the PEG moiety is included.
The potency of this product should not be compared to the potency of another pegylated or non-pegylated protein of 
the same therapeutic class. For more information, see section 5.1
Excipient(s) with known effect: 
Each pre-filled syringe contains 30 mg sorbitol (E420)
Each pre-filled syringe contains less than 1 mmol (23 mg) sodium (see section 4.4).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Solution for injection. 
Clear, colourless solution for injection. 
4. Clinical particulars
4.1 Therapeutic indications
Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with 
cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic 
syndromes).
4.2 Posology and method of administration
Neulasta therapy should be initiated and supervised by physicians experienced in oncology and/or haematology.
Posology
One 6 mg dose (a single pre-filled syringe) of Neulasta is recommended for each chemotherapy cycle, given at least 
24 hours after cytotoxic chemotherapy. 
Method of administration
Neulasta is injected subcutaneously. The injections should be given into the thigh, abdomen or upper arm. For 
instructions on handling of the medicinal product before administration, see section 6.6.
Paediatric population
The safety and efficacy of Neulasta in children has not yet been established. Currently available data are described in 
sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made 
Patients with renal impairment
No dose change is recommended in patients with renal impairment, including those with end stage renal disease.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
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4.4 Special warnings and precautions for use
Limited clinical data suggest a comparable effect on time to recovery of severe neutropenia for pegfilgrastim to 
filgrastim in patients with de novo acute myeloid leukaemia (see section 5.1). However, the long-term effects of 
Neulasta have not been established in acute myeloid leukaemia; therefore, it should be used with caution in this 
patient population.
Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects may be seen on 
some non-myeloid cells in vitro. 
The safety and efficacy of Neulasta have not been investigated in patients with myelodysplastic syndrome, chronic 
myelogenous leukaemia, and in patients with secondary Acute Myeloid Leukaemia (AML); therefore, it should not be 
used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic 
myeloid leukaemia from acute myeloid leukaemia. 
The safety and efficacy of Neulasta administration in de novo AML patients aged < 55 years with cytogenetics t
(15;17) have not been established.
The safety and efficacy of Neulasta have not been investigated in patients receiving high dose chemotherapy. This 
medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage 
regimens.
Pulmonary adverse events
Uncommon (≥1/1,000 to < 1/100) pulmonary adverse reactions, in particular interstitial pneumonia, have been 
reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at 
higher risk (see section 4.8).
The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary 
infiltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of 
Acute Respiratory Distress Syndrome (ARDS). In such circumstances Neulasta should be discontinued at the 
discretion of the physician and the appropriate treatment given (see section 4.8).
Glomerulonephritis
Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of 
glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is 
recommended.
Capillary leak syndrome 
Capillary leak syndrome has been reported after granulocyte-colony stimulating factor administration and is 
characterised by hypotension, hypoalbuminaemia, oedema and hemoconcentration. Patients who develop symptoms 
of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may 
include a need for intensive care (see section 4.8).
Splenomegaly and splenic rupture
Uncommon but generally asymptomatic cases of splenomegaly and uncommon cases of splenic rupture, including 
some fatal cases, have been reported following administration of pegfilgrastim (see section 4.8). Therefore, spleen 
size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be 
considered in patients reporting left upper abdominal pain or shoulder tip pain.
Thrombocytopenia and anaemia
Treatment with Neulasta alone does not preclude thrombocytopenia and anaemia because full dose 
myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and 
haematocrit is recommended. Special care should be taken when administering single or combination 
chemotherapeutic agents which are known to cause severe thrombocytopenia.
Sickle cell anaemia 
Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell 
disease (see section 4.8). Therefore, physicians should use caution when prescribing Neulasta in patients with sickle 
cell trait or sickle cell disease, should monitor appropriate clinical parameters and laboratory status and be attentive to 
the possible association of this medicine with splenic enlargement and vaso-occlusive crisis.
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Leukocytosis 
White blood cell (WBC) counts of 100 x 109/l or greater have been observed in less than 1% of patients receiving 
Neulasta. No adverse events directly attributable to this degree of leukocytosis have been reported. Such elevation in 
white blood cells is transient, typically seen 24 to 48 hours after administration and is consistent with the 
pharmacodynamic effects of this medicine. Consistent with the clinical effects and the potential for leukocytosis, a 
WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 x 109/l after the 
expected nadir, this medicine should be discontinued immediately.
Hypersensitivity
Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have been reported in 
patients treated with Neulasta. Permanently discontinue Neulasta in patients with clinically significant hypersensitivity. 
Do not administer Neulasta to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a serious 
allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. 
Immunogenicity 
As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against 
pegfilgrastim is generally low. Binding antibodies do occur as expected with all biologics; however, they have not 
been associated with neutralising activity at present. 
The safety and efficacy of Neulasta for the mobilisation of blood progenitor cells in patients or healthy donors has not 
been adequately evaluated. 
The needle cap of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic 
reactions.
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with 
transient positive bone imaging findings. This should be considered when interpreting bone-imaging results.
Neulasta contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this 
medicine.
Neulasta contains less than 1 mmol (23 mg) sodium per 6 mg dose, i.e. essentially 'sodium-free'.
In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade name of the 
administered product should be clearly recorded in the patient file.
4.5 Interaction with other medicinal products and other forms of interaction
Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, Neulasta should be 
administered at least 24 hours after administration of cytotoxic chemotherapy. In clinical trials, Neulasta has been 
safely administered 14 days before chemotherapy. Concomitant use of Neulasta with any chemotherapy agent has 
not been evaluated in patients. In animal models concomitant administration of Neulasta and 5-fluorouracil (5-FU) or 
other antimetabolites has been shown to potentiate myelosuppression.
Possible interactions with other haematopoietic growth factors and cytokines have not been specifically investigated 
in clinical trials. 
The potential for interaction with lithium, which also promotes the release of neutrophils, has not been specifically 
investigated. There is no evidence that such an interaction would be harmful.
The safety and efficacy of Neulasta have not been evaluated in patients receiving chemotherapy associated with 
delayed myelosuppression e.g., nitrosoureas.
Specific interaction or metabolism studies have not been performed, however, clinical trials have not indicated an 
interaction of Neulasta with any other medicinal products. 
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of pegfilgrastim in pregnant women. Studies in animals have 
shown reproductive toxicity (see section 5.3). Neulasta is not recommended during pregnancy and in women of 
childbearing potential not using contraception.
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Women who become pregnant during Neulasta treatment are encouraged to enrol in Amgen's Pregnancy 
Surveillance Programme. Contact details are provided in section 6 of the Package leaflet.
Breast-feeding
There is insufficient information on the excretion of Neulasta / metabolites in human milk, a risk to the 
newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to 
discontinue/abstain from Neulasta therapy taking into account the benefit of breast-feeding for the child and the 
benefit of therapy for the woman. 
Women who are breast-feeding during Neulasta treatment are encouraged to enrol in Amgen's Lactation Surveillance 
programme. Contact details are provided in section 6 of the Package leaflet. 
Fertility
Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses 
approximately 6 to 9 times higher than the recommended human dose (based on body surface area) (see section 
5.3).
4.7 Effects on ability to drive and use machines
Neulasta has no or negligible influence on the ability to drive and use machines. 
4.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and musculoskeletal pain 
(common). Bone pain was generally of mild to moderate severity, transient and could be controlled in most patients 
with standard analgesics. 
Hypersensitivity-type reactions, including skin rash, urticaria, angioedema, dyspnoea, erythaema, flushing, and 
hypotension occurred on initial or subsequent treatment with Neulasta (uncommon [≥ 1/1,000 to < 1/100]). Serious 
allergic reactions, including anaphylaxis can occur in patients receiving Neulasta (uncommon) (see section 4.4).
Capillary Leak Syndrome, which can be life-threatening if treatment is delayed, has been reported as uncommon (≥ 
1/1,000 to < 1/100) in cancer patients undergoing chemotherapy following administration of granulocyte colony-
stimulating factors; see section 4.4 and section “Description of selected adverse reactions” below.
Splenomegaly, generally asymptomatic, is uncommon. 
Splenic rupture including some fatal cases is uncommonly reported following administration of pegfilgrastim (see 
section 4.4). 
Uncommon pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema, pulmonary infiltrates 
and pulmonary fibrosis have been reported. Uncommonly, cases have resulted in respiratory failure or Acute 
Respiratory Distress Syndrome (ARDS), which may be fatal (see section 4.4).
Isolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle cell disease 
(uncommon in sickle cell patients) (see section 4.4).
Tabulated summary of adverse reactions
The data in the table below describe adverse reactions reported from clinical trials and spontaneous reporting. Within 
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
MedDRA system 
organ class
Adverse reactions
Very common
(≥ 1/10)
Common
(≥ 1/100 to < 1/10)
Uncommon
(≥ 1/1,000 to < 
1/100)
Rare
(≥ 1/10,000 
to < 1/1,000)
Very rare
(< 1/10,000)
Blood and 
lymphatic system 
disorders
Thrombocytopenia1
Leukocytosis1
Sickle cell crisis2; 
Splenomegaly2; 
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Splenic rupture2
Immune system 
disorders
Hypersensitivity 
reactions; 
Anaphylaxis 
Metabolism and 
nutrition disorders
Elevations in uric 
acid 
Nervous system 
disorders
Headache1
Vascular disorders
Capillary leak 
syndrome1
Respiratory, 
thoracic and 
mediastinal 
disorders
Acute Respiratory 
Distress Syndrome2; 
Pulmonary adverse 
reactions (interstitial 
pneumonia, 
pulmonary oedema, 
pulmonary infiltrates 
and pulmonary 
fibrosis) 
Gastrointestinal 
disorders
Nausea1
Skin and 
subcutaneous 
tissue disorders
Sweet's syndrome 
(acute febrile 
dermatosis)1,2;
Cutaneous 
vasculitis1,2
Musculoskeletal 
and connective 
tissue disorders
Bone pain 
Musculoskeletal pain 
(myalgia, arthralgia, 
pain in extremity, 
back pain, musculo-
skeletal pain, neck 
pain) 
General disorders 
and administrative 
site conditions
Injection site pain1
Non-cardiac chest 
pain
Injection site 
reactions2
Investigations
Elevations in lactate 
dehydrogenase and 
alkaline 
phosphatase1; 
Transient elevations 
in LFT's for ALT or 
AST1
Renal and urinary 
disorders
Glomerulonephritis2
1 See section “Description of selected adverse reactions” below.
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2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised, controlled 
clinical trials in adults. The frequency category was estimated from a statistical calculation based upon 1576 patients 
receiving Neulasta in nine randomized clinical trials.
Description of selected adverse reactions
Uncommon cases of Sweet's syndrome have been reported, although in some cases underlying haematological 
malignancies may play a role. 
Uncommon events of cutaneous vasculitis have been reported in patients treated with Neulasta. The mechanism of 
vasculitis in patients receiving Neulasta is unknown.
Injection site reactions, including injection site erythaema (uncommon (≥ 1/1000 to < 1/100)) as well as injection site 
pain (common events ≥ 1/100 to < 1/10) have occurred on initial or subsequent treatment with Neulasta.
Common (≥ 1/100 to < 1/10) cases of leukocytosis (White Blood Count [WBC] > 100 x 109/l) have been reported (see 
section 4.4).
Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated clinical effects, 
were uncommon; reversible, mild to moderate elevations in lactate dehydrogenase, with no associated clinical effects, 
were uncommon in patients receiving Neulasta following cytotoxic chemotherapy. 
Nausea and headaches were very commonly observed in patients receiving chemotherapy.
Uncommon elevations in liver function tests (LFTs) for ALT (alanine aminotransferase) or AST (aspartate 
aminotransferase), have been observed in patients after receiving pegfilgrastim following cytotoxic chemotherapy. 
These elevations are transient and return to baseline.
Common cases of thrombocytopenia have been reported.
Cases of capillary leak syndrome have been reported in the post marketing setting with granulocyte colony-
stimulating factor use. These have generally occurred in patients with advanced malignant diseases, sepsis, taking 
multiple chemotherapy medications or undergoing apheresis (see section 4.4).
Paediatric population
The experience in children is limited. A higher frequency of serious adverse reactions in younger children aged 0-5 
years (92%) has been observed compared to older children aged 6-11 and 12-21 years respectively (80% and 67%) 
and adults. The most common adverse reaction reported was bone pain (see section 5.1 and 5.2).
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued 
monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any 
suspected adverse reactions via: 
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace 
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
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Single doses of 300 µg/kg have been administered subcutaneously to a limited number of healthy volunteers and 
patients with non-small cell lung cancer without serious adverse reactions. The adverse events were similar to those 
in subjects receiving lower doses of pegfilgrastim.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: immunostimulants, colony stimulating factor; ATC Code: L03AA13
Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates the production and release of 
neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of recombinant human G-CSF (r-metHuG-
CSF) with a single 20 kd polyethylene glycol (PEG) molecule. Pegfilgrastim is a sustained duration form of filgrastim 
due to decreased renal clearance. Pegfilgrastim and filgrastim have been shown to have identical modes of action, 
causing a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes 
and/or lymphocytes. Similarly to filgrastim, neutrophils produced in response to pegfilgrastim show normal or 
enhanced function as demonstrated by tests of chemotactic and phagocytic function. As with other haematopoietic 
growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells. G-CSF can promote 
growth of myeloid cells, including malignant cells, in vitro and similar effects may be seen on some non-myeloid cells 
in vitro.
In two randomised, double-blind, pivotal studies in patients with high risk stage II-IV breast cancer undergoing 
myelosuppressive chemotherapy consisting of doxorubicin and docetaxel, use of pegfilgrastim, as a single once per 
cycle dose, reduced the duration of neutropenia and the incidence of febrile neutropenia similarly to that observed 
with daily administrations of filgrastim (a median of 11 daily administrations). In the absence of growth factor support, 
this regimen has been reported to result in a mean duration of grade 4 neutropenia of 5 to7 days, and a 30-40% 
incidence of febrile neutropenia. In one study (n = 157), which used a 6mg fixed dose of pegfilgrastim the mean 
duration of grade 4 neutropenia for the pegfilgrastim group was 1.8 days compared with 1.6 days in the filgrastim 
group (difference 0.23 days, 95% CI -0.15, 0.63). Over the entire study, the rate of febrile neutropenia was 13% of 
pegfilgrastim-treated patients compared with 20% of filgrastim-treated patients (difference 7%, 95% CI of -19%, 5%). 
In a second study (n = 310), which used a weight-adjusted dose (100 μg /kg), the mean duration of grade 4 
neutropenia for the pegfilgrastim group was 1.7 days, compared with 1.8 days in the filgrastim group (difference 0.03 
days, 95% CI -0.36, 0.30). The overall rate of febrile neutropenia was 9% of patients treated with pegfilgrastim and 
18% of patients treated with filgrastim (difference 9%, 95% CI of -16.8%,-1.1%).
In a placebo-controlled, double blind study in patients with breast cancer the effect of pegfilgrastim on the incidence of 
febrile neutropenia was evaluated following administration of a chemotherapy regimen associated with a febrile 
neutropenia rate of 10-20% (docetaxel 100 mg/m2 every 3 weeks for 4 cycles). Nine hundred and twenty eight 
patients were randomised to receive either a single dose of pegfilgrastim or placebo approximately 24 hours (Day 2) 
after chemotherapy in each cycle. The incidence of febrile neutropenia was lower for patients randomised to receive 
pegfilgrastim compared with placebo (1% versus 17%, p < 0.001). The incidence of hospitalisations and IV anti-
infective use associated with a clinical diagnosis of febrile neutropenia was lower in the pegfilgrastim group compared 
with placebo (1% versus 14%, p < 0.001; and 2% versus 10%, p < 0.001).
A small (n = 83), Phase II, randomised, double-blind study in patients receiving chemotherapy for de novo acute 
myeloid leukaemia compared pegfilgrastim (single dose of 6 mg) with filgrastim, administered during induction 
chemotherapy. Median time to recovery from severe neutropenia was estimated as 22 days in both treatment groups. 
Long term outcome was not studied (see section 4.4). 
In a phase II (n = 37) multicentre, randomised, open-label study of paediatric sarcoma patients receiving 100 μg/kg 
pegfilgrastim following cycle 1 of vincristine, doxorubicin and cyclophosphamide (VAdriaC/IE) chemotherapy, a longer 
duration of severe neutropenia (neutrophils < 0.5 x 109) was observed in younger children aged 0-5 yrs (8.9 days) 
compared to older children aged 6-11 years and 12-21 years (6 days and 3.7 days, respectively) and adults. 
Additionally a higher incidence of febrile neutropenia was observed in younger children aged 0-5 yrs (75%) compared 
to older children aged 6-11 years and 12-21 years (70% and 33%, respectively) and adults (see sections 4.8 and 5.2).
5.2 Pharmacokinetic properties
After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim occurs at 16 to 120 
hours after dosing and serum concentrations of pegfilgrastim are maintained during the period of neutropenia after 
myelosuppressive chemotherapy. The elimination of pegfilgrastim is non-linear with respect to dose; serum clearance 
of pegfilgrastim decreases with increasing dose. Pegfilgrastim appears to be mainly eliminated by neutrophil mediated 
clearance, which becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, the 
serum concentration of pegfilgrastim declines rapidly at the onset of neutrophil recovery (see figure 1).
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Figure 1. Profile of Median Pegfilgrastim Serum Concentration and Absolute Neutrophil Count (ANC) in 
Chemotherapy Treated Patients after a Single 6 mg Injection
Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not expected to be 
affected by renal or hepatic impairment. In an open label, single dose study (n = 31) various stages of renal 
impairment, including end-stage renal disease, had no impact on the pharmacokinetics of pegfilgrastim.
Elderly people
Limited data indicate that the pharmacokinetics of pegfilgrastim in elderly subjects (> 65 years) is similar to that in 
adults. 
Paediatric population
The pharmacokinetics of pegfilgrastim were studied in 37 paediatric patients with sarcoma, who received 100 μg/kg 
pegfilgrastim after the completion of VAdriaC/IE chemotherapy. The youngest age group (0-5 years) had a higher 
mean exposure to pegfilgrastim (AUC) (± Standard Deviation) (47.9 ± 22.5 μg·hr/ml) than older children aged 6-11 
years and 12-21 years (22.0 ± 13.1 μg·hr/ml and 29.3 ± 23.2 μg·hr/ml, respectively) (see section 5.1). With the 
exception of the youngest age group (0-5 years), the mean AUC in paediatric subjects appeared similar to that for 
adult patients with high-risk stage II-IV breast cancer and receiving 100 μg/kg pegfilgrastim after the completion of 
doxorubicin/docetaxel (see sections 4.8 and 5.1). 
5.3 Preclinical safety data
Preclinical data from conventional studies of repeated dose toxicity revealed the expected pharmacological effects 
including increases in leukocyte count, myeloid hyperplasia in bone marrow, extramedullary haematopoiesis and 
splenic enlargement. 
There were no adverse effects observed in offspring from pregnant rats given pegfilgrastim subcutaneously, but in 
rabbits pegfilgrastim has been shown to cause embryo/foetal toxicity (embryo loss) at cumulative doses 
approximately 4 times the recommended human dose, which were not seen when pregnant rabbits were exposed to 
the recommended human dose. In rat studies, it was shown that pegfilgrastim may cross the placenta. Studies in rats 
indicated that reproductive performance, fertility, oestrous cycling, days between pairing and coitus, and intrauterine 
survival were unaffected by pegfilgrastim given subcutaneously. The relevance of these findings for humans is not 
known. 
6. Pharmaceutical particulars
6.1 List of excipients
Sodium acetate*
Sorbitol (E420) 
Polysorbate 20
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Water for injections
*Sodium acetate is formed by titrating glacial acetic acid with sodium hydroxide. 
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products, particularly with sodium chloride solutions. 
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). 
Neulasta may be exposed to room temperature (not above 30°C) for a maximum single period of up to 72 hours. 
Neulasta left at room temperature for more than 72 hours should be discarded. 
Do not freeze. Accidental exposure to freezing temperatures for a single period of less than 24 hours does not 
adversely affect the stability of Neulasta.
Keep the container in the outer carton in order to protect from light. 
6.5 Nature and contents of container
Pre-filled syringe (Type I glass), with a rubber stopper and a stainless steel needle with or without an automatic 
needle guard. 
The needle cap of the pre-filled syringe contains dry natural rubber (a derivative of latex) (see section 4.4).
Each pre-filled syringe contains 0.6 ml of solution for injection. Pack size of one pre-filled syringe, in either a blistered 
or non-blistered packaging. 
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Before administration, Neulasta solution should be inspected visually for particulate matter. Only a solution that is 
clear and colourless should be injected. 
Excessive shaking may aggregate pegfilgrastim, rendering it biologically inactive. 
Allow the pre-filled syringe to reach room temperature before injecting.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
8. Marketing authorisation number(s)
EU/1/02/227/001 1 pack blistered syringe
EU/1/02/227/002 1 pack unblistered syringe
EU/1/02/227/004 1 pack blistered syringe with needle guard
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 22 August 2002
Date of latest renewal: 16 July 2007
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Address
240 Cambridge Science Park, Milton Road, 
Cambridge, CB4 0WD
Fax
+44 (0)1223 426 314
Medical Information e-mail
gbinfoline@amgen.com
Medical Information Fax
+44 (0)1223 426 314
Telephone
+44 (0)1223 420 305
Medical Information Direct Line
+44 (0)1223 436 441
Customer Care direct line
+44 (0)808 0100 321
10. Date of revision of the text
May 2015
Detailed information on this medicinal product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu
Company Contact Details
Amgen Ltd
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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
 
Appendix G. Protocol Amendment Complete Listing of Changes 
The following specific changes have been incorporated into the protocol under this protocol 
amendment.  Sections from the original protocol that have been changed are detailed below 
and the new text to each changed section has been added.  Changes that were strictly editorial 
(e.g. updating, formatting, correction of spelling errors etc.) are not included. 
1. Title Page and Synopsis: Study Title 
Existing Text: 
A Phase 1-2 ascending dose study to assess the pharmacodynamics, pharmacokinetics, and 
safety of HSP-130 in subjects with non-metastatic breast cancer following single dose and 
multiple-dose administration by subcutaneous injection. 
Revised Text: 
A Phase 1-2 ascending dose study to assess the pharmacodynamics, pharmacokinetics, and 
safety of HSP-130 in subjects with non-metastatic breast cancer following single-dose and 
multiple-dose administration by subcutaneous injection. 
Rationale for Change: 
Inserted hyphen for grammatical correction and as well as for consistency. 
 
2. Modified Protocol Version and Date 
Existing Text: 
IND Number 
124793 
EudraCT Number 
2015-002057-35 
Sponsor 
Hospira, Inc. (Hospira) 
 
Hospira, Inc. 
275 North Field Drive 
Lake Forest, IL 60045 
Original Protocol v 2.0 
31 July 2015 
Amendment #2, Protocol v 2.6 
17 December 2015 
 
 
 
Page 108 of 145 
 


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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Rationale for Change: 
Choice of one specific regimen to limit chemotherapy-induced heterogeneity. 
6. Synopsis: Key Inclusion Criteria for all study subjects and Section 4.2: 
Inclusion criteria 
Existing Text: 
Chemotherapy naïve, who have not received chemotherapy in the neoadjuvant setting and 
who are candidates for chemotherapy in the adjuvant setting of 
taxane/cyclophosphamide-based regimen, e.g.,TAC or TC as background chemotherapy 
Revised Text: 
Chemotherapy naïve, who have not received chemotherapy in the neoadjuvant setting and 
who are candidates for chemotherapy in the adjuvant setting of 
taxane/cyclophosphamide-based regimen, i.e.,TAC as background chemotherapy 
Rationale for Change: 
Choice of one specific regimen to limit chemotherapy-induced heterogeneity. 
 
7. Synopsis: Key Exclusion Criteria and Section 4.3: Exclusion criteria 
Existing Text: 
Chemotherapy other than that included in this study (i.e., taxane/cyclophosphamide-based 
regimen, e.g., TAC or TC) or neoadjuvant chemotherapy; or known immunosuppressive 
agents including chronic oral corticosteroid use, or radiation therapy within 4 weeks of first 
dose of HSP-130, prior bone marrow or stem cell transplantation, or malignancy within 
5 years 
Revised Text: 
Chemotherapy other than that included in this study (i.e., taxane/cyclophosphamide-based 
regimen, i.e., TAC) or neoadjuvant chemotherapy; or known immunosuppressive agents 
including chronic oral corticosteroid use, or radiation therapy within 4 weeks of first dose of 
HSP-130, prior bone marrow or stem cell transplantation, or malignancy within 5 years 
Rationale for Change: 
Choice of one specific regimen to limit chemotherapy-induced heterogeneity. 
 
 
Page 111 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
8. Synopsis: Duration of Treatment, Safety Assessments, Section 1.5.3: 
Dosing Regimen and Treatment Duration, Section 2.3: Safety Variables and 
Section 3.3: Estimated Study Duration 
Existing Text: 
Subjects receiving Regimen B (6 mg), and, if performed, multiple dose Regimen A (3 mg) 
[and Regimen C (12 mg) if the decision is made with the FDA to pursue a 12 mg dose. See 
Section 6.3.2 for details], will receive up to 4 doses of HSP-130 in the context of 4 cycles of 
chemotherapy (21 days per cycle). 
Revised Text: 
Subjects receiving Regimen B (6 mg), and, if performed, multiple dose Regimen A (3 mg) 
[and Regimen C (12 mg) if the decision is made with the FDA to pursue a 12 mg dose. See 
Section 6.3.2 for details], will receive up to 4 doses of HSP-130 in the context of 4 cycles of 
chemotherapy (≥ 21 days per cycle). 
Rationale for Change: 
To clarify that chemotherapy cycles will be at least 21 days in duration. 
 
9. Synopsis: Pharmacodynamics and Pharmacokinetics of HSP-130 
Existing Text: 
Cycle 0: 
Pharmacodynamic Sampling/Collection: 
Blood samples for ANC (4.0 mL) and CD34+ count (4.0 mL) will be collected by 
venipuncture into evacuated collection tubes within 1 hour prior to dose administration on 
Day 1 and at 48, 96, 144, 192, 240, and 312 hours post-dose. 
Cycles 1-4:  
Pharmacodynamic Sampling/Collection: 
Blood samples for ANC (4.0 mL) will be collected by venipuncture into evacuated collection 
tubes within 1 hour prior to dose administration on Day 2 of the chemotherapy cycle and at 
48, 96, 144, 192, 240, and 312 hours post-dose.  This sample collection schedule will be 
applied to Cycles 1 and 4 with HSP-130 treatment groups. 
 
 
 
Page 112 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Revised Text: 
Cycle 0: 
Pharmacodynamic Sampling/Collection: 
Blood samples for ANC (2.7 mL) and CD34+ count (2.0 mL) will be collected by 
venipuncture into evacuated collection tubes within 1 hour prior to dose administration on 
Day 1 and at 48, 96, 144, 192, 240, and 312 hours post-dose. 
Cycles 1-4:  
Pharmacodynamic Sampling/Collection: 
Blood samples for ANC (2.7 mL) will be collected by venipuncture into evacuated collection 
tubes within 1 hour prior to dose administration on Day 2 of the chemotherapy cycle and at 
48, 96, 144, 192, 240, and 312 hours post-dose.  This sample collection schedule will be 
applied to Cycles 1 and 4 with HSP-130 treatment groups. 
Rationale for Change: 
Different collection tube size allowed for smaller volume to be collected. 
 
10. Synopsis: Safety Assessments and Section 2.3 Safety Variables 
Existing Text: 
Cycles 1-4: 
In subjects who experience FN and/or ANC < 0.5 x 109/L for > 1 week, severe or cumulative 
cutaneous reactions, or severe (grade 3 or 4) peripheral neuropathy during therapy, the dose 
of docetaxel will be reduced by 20% or as deemed appropriate by treating physician. 
Doxorubicin will be reduced by 25% in subjects with FN and /or ANC < 0.5 x 109/L 
for > 1 week or as deemed appropriate by treating physician.  In subjects with a platelet count 
of < 20 x 109/L and/or failure to recover to ≥ 100 x 109/L by Day 20 of a cycle, dosages of 
doxorubicin and docetaxel will to be reduced by 25% in subsequent cycles or as deemed 
appropriate by treating physician.  If reactions continue at the reduced chemotherapy doses, 
study treatment will be discontinued and the subject will be withdrawn.  
Revised Text: 
Cycles 1-4: 
In subjects who experience FN and/or ANC < 0.5 x 109/L for > 1 week, severe or cumulative 
cutaneous reactions, or severe (grade 3 or 4) peripheral neuropathy during therapy, the 
chemotherapy timing and dose will be modified as deemed appropriate by treating physician. 
 
Page 113 of 145 
 


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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Rationale for Change: 
To clarify that 28-44 days is a general guideline and not protocol defined such that if 
definitive surgery is beyond 44 days, e.g., as inability of surgeon to schedule patient’s 
surgery within 44 days from study drug, this would not be a protocol deviation. 
 
13. Table 1 Schedule of Study Activities: Cycle 0: 3 mg or 6 mg SC Injection 
(s) Without Background Chemotherapy 
Existing Text: 
Table 1. 
Schedule of Study Activities: Cycle 0: 3 mg or 6 mg SC Injection 
(s) Without Background Chemotherapy 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visit  
30 (± 2) 
Study Day 
-14 to -1 
1 
2 
3 
5 
7 
9 11 14 20 
Clinical Assessments/Activities 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
X 
Body Weight & Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CISNE b  
 
X 
 
 
 
X 
 
 
 
X 
X 
FACT-N 
 
X 
 
 
 
 
 
 
 
X 
X 
Pregnancy Test c 
X 
 
 
 
 
 
 
 
 
 
X 
HSP-130 Administration 
 
X 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
X 
Chest X-ray (if none within 
1 month) 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments d 
Clinical Chemistry 
X 
 
 
X 
 
 
 
 
 
 
X 
Hematology (including 
complete blood count + 
Platelets) 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Serology (anti-HIV Abs) 
X 
 
 
 
 
 
 
 
 
 
 
 
Page 115 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Table 1. 
Schedule of Study Activities: Cycle 0: 3 mg or 6 mg SC Injection 
(s) Without Background Chemotherapy 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visit  
30 (± 2) 
Study Day 
-14 to -1 
1 
2 
3 
5 
7 
9 11 14 20 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic Sampling e  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Pharmacokinetic Sampling f  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Anti-HSP-130 antibody 
Sampling g 
 
X 
 
 
 
 
 
 
X 
X 
 
a. Vital Signs will be measured pre-dose, at approximately the same time at Day 1, each day of PK/PD 
sampling (Day 2-Day 14), Day 20 and at Follow-up Visit 
b. Clinical Index of Stable Febrile Neutropenia (CISNE) : assessment will be completed for each episode of 
febrile neutropenia 
c. Serum pregnancy test for all subjects except those who are postmenopausal for 5 years or have undergone 
surgical sterilization 
d. The total blood volume for all laboratory assessments is approximately 200 mL 
e. Pharmacodynamic sampling for absolute neutrophil count (ANC), CD34+ count will be collected within 
1 hour prior to dose administration and at 48, 96, 144, 192, 240, and 312 hours post-dose 
f. Pharmacokinetic sampling will be collected within 1 hour prior to dose at Day 1, and at 6, 12, 24, 48, 96, 
144, 192, 240, and 312 hours post-dose 
g. Anti-HSP-130 antibody sampling will be collected pre-dose on Day 1 as well as on Day 14 and Day 20. 
Revised Text: 
Table 1. 
Schedule of Study Activities: Cycle 0: 3 mg or 6 mg SC Injection 
(s) Without Background Chemotherapy 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visit  
30 (± 2) 
Study Day 
-14 to -1 
1 
2 
3 
5 
7 
9 11 14 20 
Clinical Assessments/Activities 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
X 
Body Weight & Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Page 116 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Table 1. 
Schedule of Study Activities: Cycle 0: 3 mg or 6 mg SC Injection 
(s) Without Background Chemotherapy 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visit  
30 (± 2) 
Study Day 
-14 to -1 
1 
2 
3 
5 
7 
9 11 14 20 
CISNE b  
 
X 
 
 
 
X 
 
 
 
X 
X 
FACT-N c 
 
X 
 
 
 
 
 
 
 
X 
X 
Pregnancy Test d 
X 
 
 
 
 
 
 
 
 
 
X 
HSP-130 Administration 
 
X 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
X 
Chest X-ray (if none within 
1 month) 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments e 
Clinical Chemistry 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Hematology (including 
complete blood count + 
Platelets) 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Serology (anti-HIV Abs) 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
X 
Spot urine for protein/creatinine 
ratio (PCR) 
X 
 
 
X 
 
 
 
X 
 
X 
X 
Pharmacodynamic Sampling f  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Pharmacokinetic Sampling g  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Anti-HSP-130 antibody 
Sampling h 
 
X 
 
 
 
 
 
 
X 
X 
 
a. Vital Signs will be measured pre-dose, at approximately the same time at Day 1, each day of PK/PD 
sampling (Day 2-Day 14), Day 20 and at Follow-up Visit 
b. Clinical Index of Stable Febrile Neutropenia (CISNE) : assessment will be completed for each episode of 
febrile neutropenia 
c. As available in local language 
d. Serum pregnancy test for all subjects except those who are postmenopausal for 5 years or have undergone 
surgical sterilization 
e. The total blood volume for all laboratory assessments is approximately 100 mL 
f. Pharmacodynamic sampling for absolute neutrophil count (ANC), CD34+ count will be collected within 
1 hour prior to dose administration and at 48, 96, 144, 192, 240, and 312 hours post-dose 
g. Pharmacokinetic sampling will be collected within 1 hour prior to dose at Day 1, and at 6, 12, 24, 48, 96, 
144, 192, 240, and 312 hours post-dose 
h. Anti-HSP-130 antibody sampling will be collected pre-dose on Day 1 as well as on Day 14 and Day 20. 
 
 
Page 117 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Rationale for Change: 
The FACT-N is a licensed, validated patient reported quality of life tool with multiple 
translations but it is not available in all languages. As of the date of this amendment, there is 
no Hungarian translation. Will be made available in English, Spanish and, if becomes 
available, in Hungarian.  
The urines to be collected during the study are primarily included for screening for 
proteinuria. It has been determined that potentially a better option than qualitative 
urinalysis/dipstick to address this would be for the semi-quantitative spot urine for PCR. 
 
14. Table 2 Schedule of Study Activities: Cycles 1 and 4 for Subjects 
Receiving 6 mg or 12 mg¥ SC Injection(s) 24 hours Post-Chemotherapy 
Administration Each Cycle* 
Existing Text: 
Table 2. 
Schedule of Study Activities: Cycles 1 and 4 for Subjects 
Receiving 6 mg or 12 mg¥ SC Injection(s) 24 hours 
Post-Chemotherapy Administration Each Cycle* 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visiti 
(Cycle 4) 
Study Day 
-14 to -1 
1 
2 
3 
4 
6 
8 
10 11 12 15 
20 
30 (± 2) 
Clinical Assessments/Activities 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs a 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
WHO Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CISNE b 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
FACT-N 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Test c 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HSP-130 
Administration d 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Page 118 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Table 2. 
Schedule of Study Activities: Cycles 1 and 4 for Subjects 
Receiving 6 mg or 12 mg¥ SC Injection(s) 24 hours 
Post-Chemotherapy Administration Each Cycle* 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visiti 
(Cycle 4) 
Study Day 
-14 to -1 
1 
2 
3 
4 
6 
8 
10 11 12 15 
20 
30 (± 2) 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
12-lead 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Chest X-Ray (if 
none within 
1 month) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments e 
Clinical Chemistry 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
Hematology 
(including 
complete blood 
count + platelets) 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Serology (anti-HIV 
Abs) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic 
Sampling f  
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Pharmacokinetic 
Sampling g  
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Anti-HSP-130 
antibody 
Sampling h 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
¥ Enrollment in the 12 mg cohort will occur only after 
• review with the FDA of data from Cycle 0 cohorts, and the Cycles 1-4 for 6 mg cohort (and 3 mg 
cohort, if performed) and 
• only if the exposure pattern of the PK/PD response suggest that higher doses are required.  Additional 
details are available regarding the 12 mg cohort and associated stopping rules in section 6.3.2. 
*If decision is made to carry out Regimen A in Cycles 1 and 4, subjects will follow same activities listed above 
a. Vital Signs will be measured pre-dose, at approximately the same time at Day 2, and each day of PK/PD 
sampling (Day 3-Day 15), Day 18, Day 20, and at Follow-up Visit 
b. Clinical Index of Stable Febrile Neutropenia (CISNE): assessment will be completed for each episode of 
febrile neutropenia 
c. Serum pregnancy test for all subjects except those who are postmenopausal for 5 years or have undergone 
surgical sterilization 
d.  In Cycles 1 and 4, subjects will receive treatment with HSP-130 on Day 2 (no less than 24 hours after 
administration of chemotherapy) 
e. The total blood volume for all laboratory assessments is approximately 350 mL 
 
Page 119 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
f. Pharmacodynamic sampling for absolute neutrophil count (ANC) will be collected within 1 hour prior to 
dose administration and at 48, 96, 144, 192, 240, and 312 hours post-dose 
g. Pharmacokinetic sampling will be collected within 1 hour prior to dose and at 6, 12, 24, 48, 96, 144, 192, 
240, and 312 hours post-dose 
h. Anti-HSP-130 antibody sampling will be collected pre-dose on Day 2 and on Day 20 
i. 
These assessments will be carried out at the end of Cycle 4 or at the time of subject termination during the 
planned course of the study 
Revised Text: 
Table 2. 
Schedule of Study Activities: Cycles 1 and 4 for Subjects 
Receiving 6 mg or 12 mg¥ SC Injection(s) 24 hours 
Post-Chemotherapy Administration Each Cycle* 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visiti 
(Cycle 4) 
Study Day 
-14 to -1 
1 
2 
3 
4 
6 
8 
10 11 12 15 
20 
30 (± 2) 
Clinical Assessments/Activities 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs a 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
WHO Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CISNE b 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
FACT-N c 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Test d 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HSP-130 
Administration e 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
12-lead 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Chest X-Ray (if 
none within 
1 month) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments f 
Clinical Chemistry 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Page 120 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Table 2. 
Schedule of Study Activities: Cycles 1 and 4 for Subjects 
Receiving 6 mg or 12 mg¥ SC Injection(s) 24 hours 
Post-Chemotherapy Administration Each Cycle* 
Evaluation 
Screening 
Site Visit 
Follow-up 
Visiti 
(Cycle 4) 
Study Day 
-14 to -1 
1 
2 
3 
4 
6 
8 
10 11 12 15 
20 
30 (± 2) 
Hematology 
(including 
complete blood 
count + platelets) 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Serology (anti-HIV 
Abs) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Spot urine for 
protein/creatinine 
ratio (PCR) 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Pharmacodynamic 
Sampling g  
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Pharmacokinetic 
Sampling h  
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Anti-HSP-130 
antibody 
Sampling i 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
¥ Enrollment in the 12 mg cohort will occur only after 
• review with the FDA of data from Cycle 0 cohorts, and the Cycles 1-4 for 6 mg cohort (and 3 mg 
cohort, if performed) and 
• only if the exposure pattern of the PK/PD response suggest that higher doses are required.  Additional 
details are available regarding the 12 mg cohort and associated stopping rules in section 6.3.2. 
*If decision is made to carry out Regimen A in Cycles 1 and 4, subjects will follow same activities listed above 
a. Vital Signs will be measured pre-dose, at approximately the same time at Day 2, and each day of PK/PD 
sampling (Day 3-Day 15), Day 18, Day 20, and at Follow-up Visit 
b. Clinical Index of Stable Febrile Neutropenia (CISNE): assessment will be completed for each episode of 
febrile neutropenia 
c. As available in local language 
d. Serum pregnancy test for all subjects except those who are postmenopausal for 5 years or have undergone 
surgical sterilization 
e.  In Cycles 1 and 4, subjects will receive treatment with HSP-130 on Day 2 (no less than 24 hours after 
administration of chemotherapy) 
f. The total blood volume for all laboratory assessments is approximately 250 mL 
g. Pharmacodynamic sampling for absolute neutrophil count (ANC) will be collected within 1 hour prior to 
dose administration and at 48, 96, 144, 192, 240, and 312 hours post-dose 
h. Pharmacokinetic sampling will be collected within 1 hour prior to dose and at 6, 12, 24, 48, 96, 144, 192, 
240, and 312 hours post-dose 
i. 
Anti-HSP-130 antibody sampling will be collected pre-dose on Day 2 and on Day 20 
j. 
These assessments will be carried out at the end of Cycle 4 or at the time of subject termination during the 
planned course of the study 
 
Page 121 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Rationale for Change: 
The FACT-N is a licensed, validated patient reported quality of life tool with multiple 
translations but it is not available in all languages. As of the date of this amendment, there is 
no Hungarian translation. Will be made available in English, Spanish and, if becomes 
available, in Hungarian.  
The urines to be collected during the study are primarily included for screening for 
proteinuria. It has been determined that potentially a better option than qualitative 
urinalysis/dipstick to address this would be for the semi-quantitative spot urine for PCR. 
 
15. Glossary of Abbreviations: 
Existing Text: 
Abbreviation/Acronym 
Definition 
TC 
docetaxel and cyclophosphamide 
Revised Text: 
Deleted TC and added the following abbreviations. 
Abbreviation/Acronym 
Definition 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
PCR 
protein/creatinine ratio 
WHO 
World Health Organization 
Rationale for Change: 
Updated for accuracy, completeness, and consistency. 
 
16. Section 1.5.4: Selection of Pharmacodynamic Endpoints 
Existing Text: 
Secondary PD parameters include DSN in Cycle 4, ANC nadir concentration, time of nadir 
concentration, area under the effect curve (AUEC), incidence of febrile neutropenia, defined 
as tympanic or axillary body temperature > 38.5°C for > 1 hour and ANC < 0.5 x 109/L, 
 
Page 122 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
incidence of severe neutropenia (grade 4) and time to ANC recovery (the first day with 
ANC ≥ 2.0 x 109/L after any day with ANC < 2.0 x 109/L) in Cycle 1 and Cycle 4. 
Revised Text: 
Secondary PD parameters include DSN in Cycle 4, ANC nadir concentration, time of nadir 
concentration, area under the effect curve (AUEC), incidence of febrile neutropenia, defined 
as tympanic or axillary body temperature > 38.5°C for > 1 hour and ANC < 1.0 x 109/L, 
incidence of severe neutropenia (grade 4, ANC < 0.5 x 109/L) and time to ANC recovery (the 
first day with ANC ≥ 2.0 x 109/L after any day with ANC < 2.0 x 109/L) in Cycle 1 and 
Cycle 4. 
Rationale for Change: 
Correction of typographical error for consistency, and accuracy. 
 
17. Section 2.5.1 Performance Status 
Existing Text: 
Table 5. The WHO/Zubrod Scale 
Revised Text: 
Table 5. The WHO/Zubrod/ECOG Scale 
Rationale for Change: 
All of these terms are used for the same performance status scale but can be variously 
referred to based on local/regional variations. This was revised for clarification. 
 
18. Section 6.2.4: Physical Examination 
Existing Text: 
A physical examination will be performed at Screening and at the Follow-up Visit (after 
Cycle 0 and after Cycle 4) or upon subject discontinuation.  
Revised Text: 
A physical examination will be performed at Screening and at the Follow-up Visit (after 
Cycle 0 and after Cycle 4) or upon subject discontinuation. Physical examination will 
specifically include physical assessment of the spleen. 
 
 
Page 123 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Rationale for Change: 
One of the risks associated with use of G-CSFs is that of splenomegaly or splenic rupture. As 
such it was felt important to underscore the importance that any and all physical 
examinations that are included in the protocol must include physical assessment of the 
spleen. 
 
19. Section 6.2.8: Clinical Laboratory Tests and Section 10.2.5: Assessment of 
Safety 
Existing Text: 
Laboratory abnormalities will be considered as AEs only if they result in discontinuation 
from the study, necessitate therapeutic intervention, and/or if the Investigator considers them 
to be AEs.  
Revised Text: 
Laboratory abnormalities will be considered as AEs only if they result in discontinuation 
from the study, necessitate therapeutic intervention, and/or if the Investigator considers them 
to be AEs. Grading of laboratory abnormalities will be according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (6). 
Existing Text: 
Treatment emergent adverse events (TEAEs) will be summarized by system organ class and 
preferred terms (PT). Descriptive statistics including N, mean, SD, minimum and maximum 
for numerical data, and counts and frequency for categorical data, will be tabulated for 
laboratory tests, and vital signs by treatment group.  
Revised Text: 
Treatment emergent adverse events (TEAEs) will be summarized by system organ class and 
preferred terms (PT). Descriptive statistics including N, mean, SD, minimum and maximum 
for numerical data, and counts and frequency for categorical data, will be tabulated for 
laboratory tests, and vital signs by treatment group. Grading of laboratory abnormalities will 
be according to the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03 (6). 
Rationale for Change: 
Grading of laboratory abnormalities clinically and within the context of clinical trials in 
oncology utilize the CTCAE and this was added for clarity and completeness. 
 
 
Page 124 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
20. Section 6.2.12: Total Blood Volume to be Collected During the Study  
Existing Text: 
For subjects who enroll in Cycle 0 group the total blood volume sampled is approximately 
347 mL, which breaks down as follows: 
• 200 mL of blood collected for clinical laboratory assessments 
•  56 mL of blood collected for PD assessments 
• 70 mL of blood collected for PK analyses 
• 21 mL of blood collected for anti-HSP-130 antibody testing 
For subjects enroll in Cycles 1-4 group the total blood volume sampled is approximately 
574 mL, which breaks down as follows: 
• 350 mL of blood collected for clinical laboratory assessments 
• 56 mL of blood collected for PD assessments 
• 140 mL of blood collected for PK analyses 
• 28 mL of blood collected for anti-HSP-130 antibody testing 
Total blood volume for subjects will include an additional 10-15 mL taken for pregnancy 
testing. 
Any additional blood that may be taken is unlikely to cause the total volume of blood to 
exceed approximately 362 mL for Cycle 0 group and 589 mL for Cycles 1-4 group. 
Revised Text: 
For subjects who enroll in Cycle 0 group the total blood volume sampled is approximately 
224 mL, which breaks down as follows: 
• 100 mL of blood collected for clinical laboratory assessments 
• 32.9 mL of blood collected for PD assessments 
• 70 mL of blood collected for PK analyses 
• 21 mL of blood collected for anti-HSP-130 antibody testing 
For subjects enroll in Cycles 1-4 group the total blood volume sampled is approximately 
456 mL, which breaks down as follows: 
 
Page 125 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
• 250 mL of blood collected for clinical laboratory assessments 
• 37.8 mL of blood collected for PD assessments 
• 140 mL of blood collected for PK analyses 
• 28 mL of blood collected for anti-HSP-130 antibody testing 
Total blood volume for subjects will include an additional 10-15 mL taken for pregnancy 
testing. 
Any additional blood that may be taken is unlikely to cause the total volume of blood to 
exceed approximately 239 mL for Cycle 0 group and 471 mL for Cycles 1-4 group. 
Rationale for Change: 
Different collection tube size allowed for smaller volume to be collected. 
 
21. Section 6.4.1: Pharmacodynamic sampling  
Existing Text: 
Cycle 0 
Blood samples for ANC (4.0 mL) and CD34+ count (4.0 mL) will be collected by 
venipuncture into evacuated collection tubes within 1 hour prior to dose administration on 
Day 1 and at 48, 96, 144, 192, 240, and 312 hours post-dose. 
The total number of samples planned for PD analysis (ANC and CD34+ count) in Cycle 0 is 
7, resulting in approximately 56 mL of blood volume. 
Cycles 1-4 
Blood samples for ANC (2.7 mL) will be collected by venipuncture into evacuated collection 
tubes within 1 hour prior to dose administration on Day 2 of the chemotherapy cycle and at 
48, 96, 144, 192, 240, and 312 hours post-dose.  This sample collection schedule will be only 
applied to Cycles 1 and 4 with HSP-130 treatment groups. 
The total number of samples planned for PD analysis (ANC) in Cycles 1 and 4 is 14, 
resulting in approximately 37.8 mL of blood volume. 
 
 
 
 
Page 126 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Revised Text: 
Cycle 0 
Blood samples for ANC (2.7 mL) and CD34+ count (2.0 mL) will be collected by 
venipuncture into evacuated collection tubes within 1 hour prior to dose administration on 
Day 1 and at 48, 96, 144, 192, 240, and 312 hours post-dose. 
The total number of samples planned for PD analysis (ANC and CD34+ count) in Cycle 0 is 
7, resulting in approximately 32.9 mL of blood volume. 
Cycles 1-4 
Blood samples for ANC (2.7 mL) will be collected by venipuncture into evacuated collection 
tubes within 1 hour prior to dose administration on Day 2 of the chemotherapy cycle and at 
48, 96, 144, 192, 240, and 312 hours post-dose.  This sample collection schedule will be only 
applied to Cycles 1 and 4 with HSP-130 treatment groups. 
The total number of samples planned for PD analysis (ANC) in Cycles 1 and 4 is 14, 
resulting in approximately 37.8 mL of blood volume. 
Rationale for Change: 
Different collection tube size allowed for smaller volume to be collected. 
 
22.  Section: 8.1.2 Adverse Events of Special Interest and Section: 10.2.5.1 
Adverse Events 
Existing Text: 
1. Potential Allergic Reactions, including Anaphylactic Reactions, Angioedema, 
Hypersensitivity 
2. Splenomegaly/Splenic Rupture 
3. Acute Respiratory Distress Syndrome 
4. Alveolar Hemorrhage  
5. Hemoptysis 
6. Leukocytosis 
7. Thrombocytopenia 
8. Capillary Leak Syndrome 
9. Cytokine Release Syndrome 
 
Page 127 of 145 
 


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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
25. Section: 10.2.5.1 Definitions of Adverse Events of Special Interest  
Existing Text: 
MedDRA version 17.1 is employed in this study to code event terms. adverse events of 
special interest are defined in the PEG-14-04 Statistical Analysis Plan. The adverse events of 
special interest were identified based on the safety profile of the originator product in 
accordance with the US prescribing information for approved US-approved G-CSFs 
(pegfilgrastim and filgrastim, Neulasta and Neupogen, respectively) and any potential 
preclinical or clinical Nivestim (Hospira filgrastim) data that may inform the safety 
characterization for HSP-130. 
The methodology employed to medically group together similar medical constructs within 
MedDRA was as follows: where a SMQ in MedDRA 17.1 exists to summarize the adverse 
event of interest, the SMQ was employed to medically group together the PTs.  In order to 
ensure adequate specificity, the SMQ narrow in MedDRA 17.1 was employed to offer a 
sensitive, but adequately specific approach to summarizing the adverse event of special 
interest.  If an SMQ was not available in MedDRA 17.1 to summarize the adverse event of 
interest, a selection of PTs was identified by the sponsor to provide a medically 
comprehensive grouping of the medical concept. The adverse events of special interest for 
HSP-130 are outlined below including the preferred terms summarized within each adverse 
event of special interest. 
Adverse Events of Special Interest: 
 
1. Potential Allergic Reactions defined by the MedDRA 17.1 SMQ Angioedema 
(narrow) and Anaphylactic Reactions (narrow) and Hypersensitivity (narrow) with 
the following PTs:  
 
Anaphylactic Reactions 
Anaphylactic 
reaction 
Anaphylactoid 
reaction 
First use syndrome 
Type I 
hypersensitivity 
Anaphylactic shock 
Anaphylactoid shock 
Kounis syndrome 
 
Anaphylactic 
transfusion reaction 
Circulatory collapse 
Shock 
 
 
Angioedema 
Allergic oedema 
Face oedema 
Lip oedema 
Small bowel 
angioedema 
Angioedema 
Gingival oedema 
Lip swelling 
Swelling face 
Circumoral oedema 
Gingival swelling 
Oculorespiratory 
syndrome 
Swollen tongue 
Conjunctival oedema Gleich’s syndrome 
Oedema mouth 
Tongue oedema 
Corneal oedema 
Hereditary 
angioedema 
Oropharyngeal 
swelling 
Tracheal oedema 
Epiglottic oedema 
Idiopathic urticaria 
Palatal oedema 
Urticaria 
 
Page 130 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Eye oedema 
Laryngeal oedema 
Periorbital oedema 
Urticaria cholinergic 
Eye swelling 
Laryngotracheal 
oedema 
Pharyngeal oedema 
Urticaria chronic 
Eyelid oedema 
Limbal swelling 
Scleral oedema 
Urticaria papular 
Mouth swelling  
Palatal swelling  
 
 
 
Hypersensitivity 
Hypersensitivity 
Documented 
hypersensitivity to 
administered drug 
Oropharyngeal 
blistering 
 
Drug hypersensitivity 
Drug eruption 
Oropharyngeal 
spasm 
 
Acute generalised 
exanthematous 
pustulosis 
 
Oropharyngeal 
swelling 
 
Administration site 
hypersensitivity 
Drug provocation 
test 
Palatal oedema 
 
Administration site 
rash 
Drug reaction with 
eosinophilia and 
systemic symptoms 
Palatal swelling 
 
Administration site 
urticaria 
Eczema 
Palisaded 
neutrophilic 
granulomatous 
dermatitis 
 
Allergic bronchitis 
Eczema infantile 
Palpable purpura 
 
Allergic colitis 
Eczema nummular 
Pathergy reaction 
 
Allergic cough 
Eczema vaccinatum 
Periorbital oedema 
 
Allergic cystitis 
Eczema vesicular 
Pharyngeal oedema 
 
Allergic eosinophilia 
Eczema weeping 
Pruritus allergic 
 
Allergic 
gastroenteritis 
Encephalitis allergic 
Radioallergosorbent 
test positive 
 
Allergic 
granulomatous 
angiitis 
Encephalopathy 
allergic 
Rash 
 
Allergic hepatitis 
Epidermal necrosis 
Rash erythematous 
 
Allergic keratitis 
Epidermolysis 
Rash follicular 
 
Allergic myocarditis 
Epidermolysis 
bullosa 
Rash generalised 
 
Allergic oedema 
Epiglottic oedema 
Rash macular 
 
Allergic otitis externa 
Erythema multiforme Rash maculo-papular  
Allergic otitis media 
Erythema nodosum 
Rash 
maculovesicular 
 
Allergic pharyngitis 
Exfoliative rash 
Rash morbilliform 
 
Allergic respiratory 
disease 
Eye allergy 
Rash neonatal 
 
 
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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Allergic respiratory 
symptom 
Eye oedema 
Rash 
papulosquamous 
 
Allergic sinusitis 
Eye swelling 
Rash pruritic 
 
Allergic transfusion 
reaction 
Eyelid oedema 
Rash pustular 
 
Allergy test positive 
Face oedema 
Rash rubelliform 
 
Allergy to 
immunoglobulin 
therapy 
First use syndrome 
Rash scarlatiniform 
 
Allergy to vaccine 
Giant papillary 
conjunctivitis 
Rash vesicular 
 
Alveolitis allergic 
Gingival oedema 
Reaction to azo-dyes 
 
Anaphylactic reaction Gingival swelling 
Reaction to 
colouring 
 
Anaphylactic shock 
Gleich's syndrome 
Reaction to drug 
excipients 
 
Anaphylactic 
transfusion reaction 
Haemorrhagic 
urticaria 
Reaction to 
preservatives 
 
Anaphylactoid 
reaction 
Hand dermatitis 
Red man syndrome 
 
Anaphylactoid shock 
Henoch-Schonlein 
purpura 
Rhinitis allergic 
 
Anaphylaxis 
treatment 
Henoch-Schonlein 
purpura nephritis 
Scleral oedema 
 
Angioedema 
Heparin-induced 
thrombocytopenia 
Scleritis allergic 
 
Antiallergic therapy 
Hereditary 
angioedema 
Scrotal oedema 
 
Antiendomysial 
antibody positive 
 
Serum sickness 
 
Anti-neutrophil 
cytoplasmic antibody 
positive vasculitis 
Hypersensitivity 
vasculitis 
Serum sickness-like 
reaction 
 
Application site 
dermatitis 
Idiopathic urticaria 
Shock 
 
Application site 
eczema 
Immediate post-
injection reaction 
Skin necrosis 
 
Application site 
hypersensitivity 
Immune 
thrombocytopenic 
purpura 
Skin reaction 
 
Application site rash 
Immune tolerance 
induction 
Skin test positive 
 
Application site 
urticaria 
Implant site 
dermatitis 
Small bowel 
angioedema 
 
Arthritis allergic 
Implant site 
hypersensitivity 
Solar urticaria 
 
 
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Protocol ZIN-130-1504  
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Aspirin-exacerbated 
respiratory disease 
Implant site rash 
Solvent sensitivity 
 
Atopy 
Implant site urticaria 
Stevens-Johnson 
syndrome 
 
Blepharitis allergic 
Incision site 
dermatitis 
Stoma site 
hypersensitivity 
 
Blood 
immunoglobulin E 
abnormal 
Incision site rash 
Stoma site rash 
 
Blood 
immunoglobulin E 
increased 
Infusion site 
dermatitis 
Swelling face 
 
Bromoderma 
Infusion site eczema 
Swollen tongue 
 
Bronchospasm 
Infusion site 
hypersensitivity 
Tongue oedema 
 
Catheter site 
dermatitis 
Infusion site rash 
Toxic epidermal 
necrolysis 
 
Catheter site eczema 
Infusion site urticaria Toxic skin eruption 
 
Catheter site 
hypersensitivity 
Infusion site 
vasculitis 
Tracheal oedema 
 
Catheter site rash 
Injection site 
dermatitis 
Type I 
hypersensitivity 
 
Catheter site urticaria 
Injection site 
hypersensitivity 
Type II 
hypersensitivity 
 
Catheter site 
vasculitis 
Injection site rash 
Type III immune 
complex mediated 
reaction 
 
Chronic eosinophilic 
rhinosinusitis 
Injection site 
urticaria 
Type IV 
hypersensitivity 
reaction 
 
Chronic hyperplastic 
eosinophilic sinusitis 
Injection site 
vasculitis 
Urticaria 
 
Circulatory collapse 
Interstitial 
granulomatous 
dermatitis 
Urticaria cholinergic 
 
Circumoral oedema 
Iodine allergy 
Urticaria chronic 
 
Conjunctival oedema 
Kaposi's 
varicelliform 
eruption 
Urticaria contact 
 
Conjunctivitis allergic Kounis syndrome 
Urticaria papular 
 
Contact stomatitis 
Laryngeal oedema 
Urticaria physical 
 
Contrast media 
allergy 
Laryngitis allergic 
Urticaria pigmentosa 
 
Contrast media 
reaction 
Laryngospasm 
Urticaria vesiculosa 
 
Corneal oedema 
Laryngotracheal 
Vaccination site 
 
 
Page 133 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
oedema 
dermatitis 
Cutaneous vasculitis 
Limbal swelling 
Vaccination site 
exfoliation 
 
Dennie-Morgan fold 
Lip oedema 
Vaccination site 
hypersensitivity 
 
Dermatitis 
Lip swelling 
Vaccination site rash 
 
Dermatitis acneiform 
Mouth swelling 
Vaccination site 
urticaria 
 
Dermatitis allergic 
Mucocutaneous rash 
Vaccination site 
vesicles 
 
Dermatitis atopic 
Multiple allergies 
Vaginal exfoliation 
 
Dermatitis bullous 
Nephritis allergic 
Vaginal ulceration 
 
Dermatitis contact 
Nikolsky's sign 
Vasculitic rash 
 
Dermatitis exfoliative 
Oculomucocutaneous 
syndrome 
Vulval ulceration 
 
Dermatitis exfoliative 
generalised 
Oculorespiratory 
syndrome 
Vulvovaginal rash 
 
Dermatitis 
herpetiformis 
Oedema mouth 
Vulvovaginal 
ulceration 
 
Dermatitis infected 
Oral allergy 
syndrome 
 
 
Dermatitis 
psoriasiform 
 
 
 
Distributive shock 
 
 
 
 
2. Splenomegaly/Splenic Rupture defined by the MedDRA v 17.1 with the following 
PT: Splenic rupture/splenomegaly 
 
3. Acute Respiratory Distress Syndrome (ARDS) defined by the MedDRA v 17.1 with 
the following PT: Acute Respiratory Distress syndrome 
 
4. Alveolar Hemorrhage/Hemoptysis defined by the MedDRA v 17.1 with the following 
PTs: Pulmonary alveolar haemorrhage and Pulmonary haemorrhage 
 
5. Alveolar Hemorrhage / Hemoptysis defined by the MedDRA v 17.1 with the 
following PT: Hemoptysis 
 
6. Leukocytosis defined by the MedDRA v 17.1 with the following PTs: 
Leukocytosis 
Lymphocytosis 
Neutrophilia 
 
Granulocytosis 
Monocytosis 
 
 
 
7. Thrombocytopenia defined by the MedDRA v 17.1 with the following PTs: 
Thrombocytopenia 
Mean platelet volume 
decreased 
 
 
Platelet production 
decreased 
Platelet count 
abnormal 
 
 
 
Page 134 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
8. Capillary leak syndrome defined by the MedDRA v 17.1 with the following PT: 
Capillary leak syndrome 
 
9. Cytokine release syndrome defined by the MedDRA v 17.1 with the following PT: 
Cytokine release syndrome 
 
10. Cutaneous manifestations defined by the MedDRA v 17.1 with the following PTs: 
Drug eruption 
Rash pruritic 
Drug rash 
Skin vasculitis 
Rash maculopapular 
Allergic rash 
Allergic vasculitis 
Vasculitis allergic 
Hypersensitivity 
vasculitis 
Cutaneous vasculitis 
Cutaneous 
hypersensitivity 
 
 
An AE will be considered to be treatment-emergent if the event started or worsened in 
severity after the HSP-130 administration up to and including 30 days post HSP-130 
administration.  For TEAEs, the number and percentage of subjects who reported each PT 
will be summarized by treatment groups.  Category of severity (mild, moderate, severe) and 
relationship to HSP-130 (related, not related) will be summarized by treatment group for 
TEAEs.  Adverse events missing an indicated relationship to HSP-130 will be considered 
related to HSP-130. 
SAEs will be summarized by each treatment group and listed by each subject. 
Revised Text: 
MedDRA version 17.1 or later is employed in this study to code event terms. Adverse Events 
of Special Interest are defined in the Statistical Analysis Plan. The Adverse Events of Special 
Interest were identified based on the safety profile of the originator product in accordance 
with the US prescribing information for approved US-approved G-CSFs (pegfilgrastim and 
filgrastim, Neulasta and Neupogen, respectively) and any potential preclinical or clinical 
Nivestim (EU-approved Hospira filgrastim) data that may inform the safety characterization 
for HSP-130. 
The methodology employed to medically group together similar medical constructs within 
MedDRA was as follows: where a SMQ in MedDRA 17.1 or later exists to summarize the 
adverse event of interest, the SMQ was employed to medically group together the PTs.  In 
order to ensure adequate specificity, the SMQ narrow in MedDRA 17.1 or later was 
employed to offer a sensitive, but adequately specific approach to summarizing the adverse 
event of special interest.  If an SMQ was not available in MedDRA 17.1 or later to 
summarize the adverse event of interest, a selection of PTs was identified by the sponsor to 
provide a medically comprehensive grouping of the medical concept.   
 
An AE will be considered to be treatment-emergent if the event started or worsened in 
severity after the HSP-130 administration up to and including 30 days post HSP-130 
administration. For TEAEs, the number and percentage of subjects who reported each PT 
will be summarized by treatment groups. Category of severity (mild, moderate, severe) and 
relationship to HSP-130 (related, not related) will be summarized by treatment group for 
 
Page 135 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
TEAEs. Adverse events missing an indicated relationship to HSP-130 will be considered 
related to HSP-130. 
SAEs will be summarized by each treatment group and listed by each subject. 
Rationale for Change: 
Modified text to provide a revised definition for treatment-emergent AEs and the definition 
for AEs related to the study drug. Updated information to provide better clarity on the basis 
for the identification of Adverse Events of Special Interest for ZIN 130-1504 study. 
The Adverse Events of Special Interest section is revised to remove information on the PTs 
for each Adverse Event of Special Interest in order to harmonize this protocol with the other 
protocols across programs. Updated information to reflect that MedDRA version 17.1 or later 
will be used for coding adverse events and AESIs. 
 
26. Section 13: References 
Existing Text: 
7. Common Terminology Criteria for Adverse Events; Version 4.03, 2010. Available 
at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. Accessed on 26 July 2015. 
13. Draft Guidance for Industry, Clinical Pharmacology Data to Support of a Demonstration 
of Biosimilarity to a Reference Product, May 2014. Available at: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm397017.pdf. Accessed on 26 July 2015. 
17. FDA CDER, Guidance for Industry: Bioanalytical Method Validation, May 2001. 
Available at: http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf. 
Accessed on 26 July 2015. 
19. FDA Draft Guidance for Industry:  Immunogenicity Assessment for Therapeutic Protein 
Products.  August 2014.  Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM338856.pdf. Accessed on 26 July 2015. 
21. Gascon P, Fuhr U, Sorgel F, Kinzig-Schippers M, Makhson A, Balser S, et al. 
Development of a new G-CSF product based on biosimilarity assessment. Annals of 
oncology : official journal of the European Society for Medical Oncology / ESMO. 
2010;21(7):1419-29. 
23. FDA Draft Guidance for Industry:  Assay Development for Immunogenicity Testing of 
Therapeutic Proteins.  December 2009.  Available 
at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM192750.pdf. Accessed on 26 July 2015. 
 
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Protocol ZIN-130-1504  
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40. Questionnaries. FACIT.org [Online]. [cited 2015 Apr 16]. Avaialble 
at http://www.facit.org/FACITOrg/Questionnaires. 
41. Lubenau H, Bias P, Maly AK, Siegler KE, Mehltretter K. Pharmacokinetic and 
pharmacodynamic profile of new biosimilar filgrastim XM02 equivalent to marketed 
filgrastim Neupogen: single-blind, randomized, crossover trial. BioDrugs : clinical 
immunotherapeutics, biopharmaceuticals and gene therapy. 2009;23(1):43-51. 
42. FDA CDER, Guidance for Industry; Bioanalytical Method Validation Draft Guidance 
Revision 1, September 2013. Available 
at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guid
ances/ucm368107.pdf. Accessed on 08 July 2015. 
43. van Der Auwera P, Platzer E, Xu ZX, Schulz R, Feugeas O, Capdeville R, et al. 
Pharmacodynamics and pharmacokinetics of single doses of subcutaneous pegylated 
human G-CSF mutant (Ro 25-8315) in healthy volunteers: comparison with single and 
multiple daily doses of filgrastim. American journal of hematology. 2001;66(4):245-51. 
44. FDA Draft Guidance for Industry: Assay Development for Immunogenicity Testing of 
Therapeutic Proteins. December 2009. Available 
at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM192750.pdf. Accessed on 08 July 2015. 
Revised Text: 
6. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: 
May 28, 2009 (v4.03: June 14, 2010). U.S. Department of Health and Human Services, 
National Institutes of Health, National Cancer Institute. Available 
at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. Accessed on 23 Nov 2015. 
17. NCCN Clinical Practice Guidelines on Oncology (NCCN guidelines®), Myeloid Growth 
Factors. Version 1, 2015. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. Accessed on 
23 Nov 2015. 
19. Neupogen® (Amgen) Prescribing Information, 07/2015. Available at 
http://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf . Accessed 
on 23 Nov 2015. 
21. Yang BB, Lum P, Neumann T, Nguyen S, Roskos L. Pharmacokinetic rationale for a 
fixed-dose regimen of a sustained-duration form of filgrastim in cancer patients 
[abstract]. Blood. 2000;96(11 Suppl. 1):157b. 
23. Neulasta® (pegfilgrastim) Prescribing Information. 11/2015. Amgen Inc.  Available at: 
http://pi.amgen.com/united_states/neulasta/neulasta_pi_hcp_english.pdf. Accessed on 23 
Nov 2015. 
 
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Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
40. Questionnaries. FACIT.org [Online]. [cited 2015 Apr 16]. Available at 
http://www.facit.org/FACITOrg/Questionnaires. Accessed on 23 Nov 2015. 
41. FDA CDER, Guidance for Industry: Bioanalytical Method Validation, May 2001. 
Available at: http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf. 
Accessed on 23 Nov 2015. 
42. FDA CDER, Guidance for Industry; Bioanalytical Method Validation Draft Guidance 
Revision 1, September 2013. Available at: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm368107.pdf. Accessed on 23 Nov 2015. 
43. FDA Draft Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein 
Products. August 2014. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM338856.pdf. Accessed on 23 Nov 2015. 
44. FDA Draft Guidance for Industry: Assay Development for Immunogenicity Testing of 
Therapeutic Proteins. December 2009. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM192750.pdf. Accessed on 23 Nov 2015. 
Rationale for Change: 
Updated for accuracy. 
 
27. Appendix E. Adverse Events – Categorized as SAEs 
Existing Text: 
A. 
Abortion 
Acute liver failure 
Acute respiratory (pulmonary) failure 
Acute renal failure 
Acute adrenocortical insufficiency 
Adrenal hemorrhage 
Acute Respiratory Distress Syndrome (ARDS) 
Agranulocytosis 
Alveolitis, allergic or fibrosing 
Anemia, aplastic 
Anemia, hemolytic 
Anaphylaxis, anaphylactic shock 
 
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Protocol ZIN-130-1504  
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Anaphylactoid reaction 
Aplastic bone marrow 
Apnea (all ages) 
Asphyxia, all ages 
Asystole 
Attempted suicide 
AV Block, third degree (aka, complete heart block) 
B. 
Acute blindness 
Brain death 
Brain stem hemorrhage 
C. 
Cardiac arrest/circulatory arrest/cardiorespiratory arrest 
Cardiomyopathy 
Cavernous sinus thrombosis 
Cerebral edema 
Cerebral vascular accident (stroke) includes hemorrhagic, thrombotic, embolic strokes to any 
region of the brain 
Cheyne-Stokes Respiration 
Colitis, hemorrhagic, pseudomembranous or ulcerative 
Coma (all types) 
Convulsions (seizures), all types 
Creutzfeldt-Jakob Disease 
D. 
Deafness, acute 
Death (all types) 
Delirium 
Disseminated Intravascular Coagulation (DIC) 
E. 
Embolism, arterial 
Embolism, pulmonary 
Encephalomyelitis 
Encephalopathy 
Epiglottitis 
Erythema Multiforme 
F. 
Fibrillation, ventricular 
Fibrosis, mediastinal 
 
Page 139 of 145 
 


Protocol ZIN-130-1504  
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Fetal distress, demise 
G. 
Gangrene 
Glomerulonephritis 
Goodpasture Syndrome 
Guillain-Barre Syndrome 
H. 
Hemolytic-uremic syndrome 
Hemorrhage, all intracranial 
Hemorrhage, neonatal 
Hemorrhage, retroperitoneal 
Hepatitis, infectious and non-infectious 
Hemopericardium 
Hemothorax 
Hepatic encephalopathy 
Hepatic failure, necrosis 
Hepatocellular damage, neonatal 
Hepato-renal syndrome 
Hyperpyrexia, Malignant (“Malignant Hyperthermia”) 
I. 
Intestinal ischemia, necrosis or death 
Intestinal perforation or stenosis 
Intrauterine death 
L. 
Laryngeal edema 
Leukemia 
Leukoencephalopathy, reversible or posterior multifocal 
Lymphoma 
M. 
Malignancy, primary occurrence (Excludes non-melanotic skin cancer) 
Malignant hypertension 
Manic reaction 
Meningitis 
MS aggravation or MS like syndrome 
Myelitis 
Myeloproliferative disorder 
Myocardial infarction 
 
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Protocol ZIN-130-1504  
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Myocarditis 
Myositis 
N. 
Neonatal respiratory failure 
Nephritis 
Nephropathy, toxic 
Neuroleptic Malignant Syndrome 
O. 
Optic nerve atrophy, neuritis 
P. 
Pancreatitis 
Pancytopenia 
Pemphigus 
Peritonitis 
Phlebitis, deep (DVT) 
Pleural fibrosis 
Polyarteritis Nodosa 
Pregnancy, ectopic 
Pulmonary hypertension, primary 
Pulmonary fibrosis 
Pulmonary hemorrhage, infarction 
Pulmonary embolism 
Pulmonary edema (acute) 
Pure Red Cell Aplasia (PRCA) 
Purpura  
Psychosis, acute onset 
Q. 
Quadriplegia 
R. 
Red cell aplasia 
Renal failure, acute 
Renal Tubular Necrosis 
Respiratory distress Syndrome (neonatal) 
Respiratory arrest 
Respiratory depression, neonatal 
Respiratory paralysis 
Retrobulbar neuritis 
 
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Protocol ZIN-130-1504  
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Retroperitoneal Fibrosis 
Reye’s syndrome 
Rhabdomyolysis  
S. 
Sagittal Sinus Thrombosis 
Sclerosing syndromes 
Seizure 
Serotonin Syndrome 
Status asthmaticus 
Status epilepticus 
Stevens-Johnson Syndrome 
Stillbirth 
Subarachnoid hemorrhage 
Subdural hemorrhage/hematoma 
Sudden Infant Death Syndrome (SIDS) 
T. 
Thrombocytopenia with platelet count < 50,000 (severe) 
Thromboembolism 
Thrombosis (excluding superficial sites) 
Torsades De Pointes 
Toxic Epidermal Necrolysis 
U. 
Uterine perforation 
V. 
Vasculitis 
W. 
Wallenberg Syndrome 
Withdrawal syndrome 
Revised Text: 
A: Abortion (non-elective); Acute respiratory (pulmonary) failure; Adrenal hemorrhage; 
Agranulocytosis; Anemia, aplastic; Anaphylaxis, anaphylactic shock; Anaphylactoid 
reaction; Aorto-oesophageal fistula, Aplastic bone marrow; Apnea (all ages); Asphyxia (all 
ages); Asystole; Attempted suicide; AV Block, third degree (aka, complete heart block) 
B: Acute blindness; Brain death 
C: Cardiac arrest/circulatory arrest/cardiorespiratory arrest; Cavernous sinus thrombosis; 
Cerebral edema; Cerebral vascular accident (stroke) includes hemorrhagic, thrombotic, 
 
Page 142 of 145 
 


Protocol ZIN-130-1504  
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embolic strokes to any region of the brain; Congenital anomalies (non-trivial); Coma (all 
types); Creutzfeldt-Jakob Disease 
D: Deafness, acute; Death (all types); Disseminated Intravascular Coagulation (DIC), 
Dysplasia; Deep vein thrombosis (DVT) 
E: Encephalomyelitis; Encephalopathy F: Fibrillation, ventricular; Fetal distress, demise 
G: Gangrene; Gastrointestinal obstruction; Gastrointestinal perforation; Gastrointestinal 
rupture; Genitourinary obstruction; Genitourinary tract rupture; Genitourinary tract 
perforation; Glaucoma 
H: Hemorrhage, neonatal; Hemorrhage, retroperitoneal; Hepatitis, infectious and non-
infectious; Hemopericardium; Hepatic encephalopathy;  Hepatic failure, necrosis; 
Hepatocellular damage, neonatal; Hepato-renal syndrome; Hyperpyrexia, Malignant 
(“Malignant Hyperthermia”) 
I: Intestinal ischemia, necrosis or death; Intrauterine death; Infarction (myocardial, 
pulmonary, etc.) 
L: Laryngeal edema; Leukemia; Liver failure; Leukoencephalopathy, reversible or posterior 
multifocal; Lymphoma 
M: Malignancy, primary occurrence. Excludes non-melanotic skin cancer; Malignant 
hypertension; Meningitis; MS aggravation or MS-like syndrome; Myelitis; 
Myeloproliferative disorder 
N: Neuroleptic Malignant Syndrome 
P: Pancytopenia; Pleural fibrosis; Pregnancy, ectopic; Pulmonary hypertension, primary; 
Pulmonary fibrosis; Pulmonary hemorrhage; Pulmonary edema (acute); Psychosis, acute 
onset 
Q: Quadriplegia 
R: Red cell aplasia; Renal failure, acute; Respiratory Distress Syndrome (neonatal); 
Respiratory arrest; Respiratory depression, neonatal; Respiratory paralysis; Respiratory 
obstruction; Respiratory tract perforation; respiratory tract rupture; Retrobulbar neuritis; 
Retinopathies; Retroperitoneal Fibrosis; Reye’s syndrome 
S: Sagittal sinus thrombosis; Sepsis/Septicemia; Status asthmaticus; Status epilepticus; 
Stevens-Johnson Syndrome; Stillbirth; Sudden Infant Death Syndrome (SIDS) 
T: Thrombocytopenia with platelet count <50,000 (severe); Thrombosis (excluding 
superficial sites); Torsades De Pointes; Toxic Epidermal Necrolysis 
 
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Protocol ZIN-130-1504  
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U: Uterine perforation 
V: Vascular occlusion 
W: Wallenberg Syndrome 
Rationale for Change: 
The AEs that are always considered SAEs was updated to the current version. 
 
28. Appendix F Neulasta® (pegfilgrastim, Amgen) Summary of Product 
Characteristics 
Existing Text: 
Summary of Product Characteristics Updated 22-Aug-2014| Amgen Ltd 
Revised Text: 
Summary of Product Characteristics Updated May-2015| Amgen Ltd 
Rationale for Change: 
Updated for accuracy. 
  
 
 
Page 144 of 145 
 


Protocol ZIN-130-1504  
Version 3.0; 22 December 2015 
 
Appendix H. 
Neulasta® (pegfilgrastim, Amgen) Package Insert 
 
 
The Neulasta Package Insert is appended below 
 
 
 
Page 145 of 145 
 


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Reference ID: 3846752 
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Reference ID: 3846752 
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Reference ID: 3846752 


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Reference ID: 3846752 


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Reference ID: 3846752 


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Reference ID: 3846752 


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Reference ID: 3846752 


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Reference ID: 3846752 


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Reference ID: 3846752 


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SAP_001.pdf: 
PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 1
A  PHASE 1-2 ASCENDING DOSE STUDY TO ASSESS THE 
PHARMACODYNAMICS, PHARMACOKINETICS, AND SAFETY OF PF-06881894 
(HSP-130) IN SUBJECTS WITH NON-METASTATIC BREAST CANCER 
FOLLOWING SINGLE-DOSE AND MULTIPLE-DOSE ADMINISTRATION BY 
SUBCUTANEOUS INJECTION
Statistical Analysis Plan


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 2
Protocol C1221002 (ZIN-130-1504)
A  PHASE 1-2 ASCENDING DOSE STUDY TO ASSESS THE 
PHARMACODYNAMICS, PHARMACOKINETICS, AND SAFETY OF PF-06881894 
(HSP-130) IN SUBJECTS WITH NON-METASTATIC BREAST CANCER 
FOLLOWING SINGLE-DOSE AND MULTIPLE-DOSE ADMINISTRATION BY 
SUBCUTANEOUS INJECTION
Statistical Analysis Plan (SAP) Amendment 1
Version:
Amendment 1
Author: 
Date:
11-DEC-2017
PPD


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................6
2.2. Study Design .............................................................................................................6
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoint(s) ..................................................................................................9
3.2. Secondary Endpoint(s) ..............................................................................................9
3.3. Other Endpoints.......................................................................................................10
3.4. Baseline Variables...................................................................................................10
3.5. Safety Endpoints .....................................................................................................10
3.5.1. Adverse Events...........................................................................................10
3.5.2. Laboratory Data,  Vital Signs, ECG and Immunogenicity.........................11
4. ANALYSIS SETS ...............................................................................................................12
4.1. Full Analysis Set .....................................................................................................12
4.2. Per Protocol Analysis Set........................................................................................12
4.3. Safety Analysis Set..................................................................................................12
4.4. Other Analysis Sets .................................................................................................12
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................12
5.1. Hypotheses and Decision Rules ..............................................................................12
5.2. General Methods .....................................................................................................12
5.3. Methods to Manage Missing Data ..........................................................................13
5.4. Primary Endpoint(s) ................................................................................................13
5.5. Secondary Endpoint ................................................................................................13
5.6. Other Endpoint(s)....................................................................................................14
5.7. Subset Analyses.......................................................................................................14
5.8. Baseline Summaries ................................................................................................14
5.9. Safety Summaries and Analyses .............................................................................15
6. INTERIM ANALYSES.......................................................................................................15


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 4
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................5
Table 2.
Subject Cohorts/Cycles...........................................................................................7
LIST OF FIGURES
Figure 1.
Overall Study Design..............................................................................................7


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 5
1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study C1221002 (ZIN-130-1504) is based on the 
protocol dated 22 December 2015.  
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Not Applicable
Amendment 1
Adding CTCAE 
grading.
Additional PD 
parameters.
Protein content 
adjusted PK 
parameters.
Responses to requests from regulatory agencies 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
will be provided for laboratory test results. 
For Cycle 0, area under the effect curve for ANC from zero to infinity (AUECANC 0-∞), area
under the effect curve from zero to infinity for CD34+ (AUECCD34+ 0-∞) will be added as 
secondary endpoints. 
The protein-content correction will be conducted for each individual’s PK parameters, 
AUC0-∞,  AUC0-t, and Cmax:  
Protein-content corrected PK parameter = Nominal Protein-content PK parameter /
(Actual protein concentration/10.0 mg/mL)
Where the actual protein concentrations are:

9.9 mg/mL for PF-06881894 (Lot 2052124),

10.0 mg/mL for PF-06881894 (Lot 2051124),

9.9 mg/mL for PF-06881894 (Lot 2459066).
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C1221002.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.


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Statistical Analysis Plan Amendment 1
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2.1. Study Objectives
Cycle 0
The primary objective of cycle 0 is to characterize the pharmacodynamic (PD) response of 
absolute neutrophil count (ANC) and CD34+ count to PF-06881894 (HSP-130) at doses of 
3 mg and 6 mg when administered as a single subcutaneous (SC) dose without chemotherapy 
to determine whether it is appropriate to study multiple doses of 3 mg with the context of 
background chemotherapy.
The secondary objectives are:
To characterize the pharmacokinetics (PK) of PF-06881894 (HSP-130) at doses of 3 mg and 
6 mg when administered as a single SC dose without background chemotherapy.
To characterize the safety of PF-06881894 (HSP-130) at doses of 3 mg and 6 mg when 
administered as a single SC dose without background chemotherapy.
Cycles 1-4
The primary objective of Cycles 1-4 is to characterize the PD response of duration of severe 
neutropenia (DSN) in Cycle 1 to PF-06881894 (HSP-130) over a range of doses when 
administered as single and multiple SC doses.
The secondary objectives are:
To characterize the PD response of ANC to PF-06881894 (HSP-130) in Cycles 1 and 4 over 
a range of doses when administered as single and multiple SC doses.
To characterize the PK of PF-06881894 (HSP-130) in Cycles 1 and 4 over a range of doses 
when administered as single and multiple SC doses.
To characterize the safety of PF-06881894 (HSP-130) over a range of doses when 
administered as single and multiple SC doses.
2.2. Study Design
This is an open-label, parallel group study characterizing the PD, PK, and safety of 
PF-06881894 (HSP-130) in subjects with non-distantly metastatic (non-Stage IV) breast 
cancer who have not previously received chemotherapy at any point prior to enrollment in 
this study (ZIN-130-1504).
There are two aspects of the study. In the initial part of the study, 6 subjects will be 
sequentially enrolled to receive PF-06881894 (HSP-130) treatment (3 mg or 6 mg by SC 
injection) without concomitant or background chemotherapy. This treatment setting will, 
therefore be referred to as Cycle 0. Patients in Cycle 0 will receive PF-06881894 (HSP-130)
during the period between biopsy and definitive surgery.


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
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The second group of subjects will receive up to 4 cycles of PF-06881894 (HSP-130), with
concomitant background chemotherapy. Patients in Cycles 1-4 will receive PF-06881894
(HSP-130) after definitive surgery. Chemotherapy will consist of every 3 week 
taxane/cyclophosphamide-based regimen, ie, docetaxel, doxorubicin and cyclophosphamide 
(TAC).
Specifics of the study design are described in Figure 1. 
Figure 1.
Overall Study Design
Table 2.
Subject Cohorts/Cycles
Cohort 
Cycle
(1) 3 mg/Cycle 0
0 (No chemotherapy)
(2) 6 mg/Cycle 0 
0 (No chemotherapy)
  (3) 6 mg/Cycles 1-4
1-4 (Chemotherapy)
(4) 3 mg/Cycles 1-4
1-4 (Chemotherapy)
(5) 12 mg/Cycles 1-4
1-4 (Chemotherapy)
Table 2 describes groups of subjects with planned regimens and they will be referred to as 
cohorts in this document. Note that Cohort 4 (3 mg/Cycles 1-4) and Cohort 5 (12 mg/
Cycles 1-4) were not administered in the study, and data for those cohorts will not be 
presented. Only those cohorts with data collected in the study (Cohorts 1-3) will be 
summarized and presented. 


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 8
Subjects in Cycle 0:
Subject eligibility will be determined during a 14-day Screening Period.  Eligible subjects 
will be enrolled sequentially to each of the PF-06881894 (HSP-130) dose groups as follows:
Regimen A: PF-06881894 (HSP-130), 3 mg, single SC injection in the deltoid region 
(n = 6).
Regimen B: PF-06881894 (HSP-130), 6 mg, single SC injection in the deltoid region 
(n = 6).
Initiation of Regimen B will be based on safety assessments in the first 5 evaluable subjects 
receiving Regimen A. This will include assessment of vital signs, concomitant medications, 
laboratory assessments including chemistry and hematology (complete blood count [CBC] 
and platelets), electrocardiogram (ECG), physical exam, and any adverse events (AEs) 
occurring post-dose administration through Day 30. The specific safety criteria for 
assessment for dose escalation are listed in Section 6.3.2 of the protocol. If, based on these 
assessments, there is no contraindication for dose escalation, screening for the subsequent 
dose level (Regimen B) can be initiated.
In Cycle 0, Day 1 is the day that the subject receives PF-06881894 (HSP-130). Subjects 
obtain a baseline assessment of ANC and CD34+ count on Day 1 prior to receipt of HSP-130. 
Subjects will return for ANC, CD34+ measurement, and PK assessment for up to a maximum 
of 7 visits after PF-06881894 (HSP-130) dosing.
After completion of Cycle 0, each of the subjects in these dosing groups will have completed 
their participation in assessment of PF-06881894 (HSP-130). 
Subjects in Cycles 1-4:
When enrollment of the 6 subjects receiving Regimen B in Cycle 0 is completed, an 
additional 12 subjects will be enrolled on Regimen B and entered in Cycle 1-4 as defined 
below. Patients in Cycles 1-4 will receive PF-06881894 (HSP-130) after definitive surgery. 
Eligible subjects will be enrolled sequentially to each of the PF-06881894 (HSP-130) dose 
groups as follows:
Regimen B: PF-06881894 (HSP-130), 6 mg, single SC injection in the deltoid region, at 
least 24 hours after administration of chemotherapy in Cycle 1, Cycle 2, Cycle 3, and Cycle 4 
(Planned n = 12).
During Cycles 1-4, subjects will receive treatment with PF-06881894 (HSP-130) at 24 hours 
after administration of chemotherapy (Day 2). Subjects will return for ANC measurement 
and PK assessment for up to an additional 7 visits after dosing.
Subjects will return for a Follow-up Visit 30 (±2) days after the dose of PF-06881894
(HSP-130) in Cycle 4.


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Statistical Analysis Plan Amendment 1
Page 9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Cycle 0
The primary pharmacodynamic variable is Area under the effect curve for ANC (AUECANC).  
The primary pharmacokinetic variable is area under the serum PF-06881894 (HSP-130)
versus time curve from the time of dose administration to time infinity (AUC0-∞) and the 
maximum observed serum PF-06881894 (HSP-130) concentration (Cmax). 
Cycles 1-4
The primary pharmacodynamics variable is duration of severe neutropenia (DSN). DSN is 
defined as days with grade 4 neutropenia (ANC < 0.5 x 109/L) in Cycle 1. The primary 
pharmacokinetic variables are  AUC0-t and Cmax in Cycle 1 and Cycle 4. 
3.2. Secondary Endpoint(s)
Cycle 0
The secondary pharmacodynamic variables are maximum effect for ANC (ANC_Emax), time 
of maximum effect for ANC (ANC Tmax), area under the effect curve for CD34+
(AUECCD34+), maximum effect for CD34+ count (CD34+_Emax), time of maximum effect for 
CD34+ count (CD34+ Tmax), area under the effect curve for ANC from zero to infinity 
(AUECANC 0-∞), area under the effect curve from zero to infinity for CD34+ (AUECCD34+ 0-∞).
The secondary pharmacokinetic variables are area under the serum PF-06881894 (HSP-130)
versus time curve from the time of dose administration to the time of last measurable 
concentration (AUC0-t), the time of maximum serum PF-06881894 (HSP-130) concentration 
(Tmax), elimination half-life (t1/2), elimination rate constant (λz), apparent clearance (CL). 
Protein-content corrected AUC0-∞, AUC0-t , Cmax will be calculated.
Cycle 1-4
The secondary pharmacodynamic variables are DSN in Cycle 4, ANC nadir, time of ANC 
nadir, area under the effect curve (AUEC), AUECANC 0-∞,  incidence of febrile neutropenia 
(FN), defined as tympanic or axillary body temperature >38.5°C for >1 hour with
ANC <1.0 x 109/L, incidence of severe neutropenia (grade 4, ANC <0.5 x 109/L) and time to 
ANC recovery (the first day with ANC ≥2.0 x 109/L after any day with ANC <2.0 x 109/L) in 
Cycle 1 and Cycle 4.
The secondary pharmacokinetic variables are AUC0-∞, Tmax, t1/2, λz, and CL in Cycle 1 and 
Cycle 4. Protein-content corrected AUC0-t, AUC0-∞, and Cmax will be calculated.


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 10
3.3. Other Endpoints
PF-06881894 (HSP-130) concentration for cohorts 1-3 and CD34+ for cohorts 1 and 2. 
ANC_Emax and ANC Tmax will also be provided as additional PD parameters for Cycle 1 and 
Cycle 4.
Safety endpoints are described in 3.5.
3.4. Baseline Variables
Baseline is defined as the last observation obtained prior to first dose of study medication. 
Demographic variables such as age, gender, and race will be summarized by cohort. 
3.5. Safety Endpoints
Safety endpoints include clinical adverse events (including AEs of Special Interest), SAEs, 
laboratory variables, vital signs, physical examination, ECGs, concomitant medication use, 
discontinuations from the study, exposure to study medication, and anti-pegfilgrastim (anti-
drug) antibodies. 
Adverse events, serious adverse events, concomitant medication use, discontinuations, and 
treatment exposure will be summarized by cohort.  Selected cycle-specific data (quantitative 
laboratory parameters, vital signs) will be summarized by cycle within cohort.
3.5.1. Adverse Events
An adverse event is considered treatment emergent relative to a given treatment if:

The event occurs for the first time during the effective duration of treatment and was not 
seen prior to the start of treatment (for example, during the baseline or run-in period), or

The event was seen prior to the start of treatment but increased in severity during 
treatment.
The effective duration of treatment is determined by the lag time.  Any event occurring 
within the lag time, whether this occurs during a break in treatment or at the end of treatment, 
is attributed to the corresponding treatment period. The lag time in the study is 30 days after 
the last dose of study drug.   
Definitions of Adverse Events of Special Interest
MedDRA version 17.1 or later will be employed in this study to code event terms. The 
methodology employed to medically group together similar medical constructs within
MedDRA will be as follows: where a Standard MedDRA query (SMQ) in MedDRA 17.1 or
later exists to summarize the AE of interest, the SMQ will be employed to medically group 
together the preferred terms. In order to ensure adequate specificity, the SMQ narrow in 
MedDRA 17.1 or later will be employed to offer a sensitive, but adequately specific
approach to summarizing the AE of Special Interest. If an SMQ was not available in 


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 11
MedDRA 17.1 or later to summarize the AE of interest, a selection of preferred terms will be
identified by the sponsor to provide a medically comprehensive grouping of the medical
concept. The AEs of Special Interest for PF-06881894 (HSP-130) are outlined below.  AEs 
of Special Interest have been identified prospectively based on the safety information of the 
pegfilgrastim-US reference product, as described in the Neulasta (pegfilgrastim, Amgen) 
Package Insert, and grouped by similar medical constructs. The AEs of Special Interest were 
further informed based on the known extension of the pharmacology of the drug as 
manifested by known clinical adverse reactions with G-CSFs.
The following events are considered AEs of Special Interest for PF-06881894 (HSP-130) and 
will be summarized by the medical concept (narrow SMQ and preferred term as appropriate):
1. Potential Allergic Reactions;
2. Splenomegaly;
3. Splenic Rupture;
4. Acute Respiratory Distress Syndrome;
5. Alveolar Hemorrhage;
6. Hemoptysis;
7. Leukocytosis;
8. Thrombocytopenia;
9. Capillary Leak Syndrome;
10. Cytokine Release Syndrome;
11. Cutaneous Vasculitis;
12. Glomerulonephritis (added as per the Safety Review Plan).
The identification of Adverse Events of Special Interests is included in the Safety Review 
Plan and may be adjusted according to Safety Review Plan. 
3.5.2. Laboratory Data, Vital Signs, ECG and Immunogenicity
Quantitative laboratory test measurements and change from baseline will be summarized by
cycle within cohorts.  All laboratory values outside the normal range will be flagged in the 
data listing.
Quantitative vital sign variables will be listed and change from baseline will be summarized 
by cycle within cohorts. 
ECG and physical exam data will be listed. 


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Statistical Analysis Plan Amendment 1
Page 12
Immunogenicity data will be summarized and listed. 
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to database lock and releasing the database and classifications 
will be documented per standard operating procedures.
4.1. Full Analysis Set
Full analysis set (FAS): All subjects who received at least 1 dose of study medication. In 
analysis of a particular parameter for a particular cohort, only those subjects who have 
sufficient data in the cycle to calculate the parameter will be included. Sufficient data is 
defined as having more than 3 measurable values where the parameter can be reliably 
calculated. PD/PK parameters will be summarized for two populations: (1) FAS and (2) FAS 
excluding subjects who have confirmed positive anti-pegfilgrastim (anti-drug) antibody test 
result.
4.2. Per Protocol Analysis Set 
Not applicable. 
4.3. Safety Analysis Set
All subjects who received at least 1 dose of study medication. 
Adverse events, serious adverse events, concomitant medication use, discontinuations, and 
treatment exposure will be summarized within the safety analysis set by cohort.  Selected 
cycle-specific data (quantitative laboratory parameters, vital signs) will be summarized 
within the safety analysis set by cycle within cohort.
4.4. Other Analysis Sets
Not applicable. 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
Not applicable. No statistical testing will be done.  The primary and secondary endpoints 
will be summarized using descriptive statistics only. 
5.2. General Methods 
Pharmacodynamic/Pharmacokinetic variables and concentration data will be calculated using 
non-compartmental methods and summarized with descriptive statistics: number of subjects, 
mean, standard deviation (SD), coefficient of variation (CV), median, minimum and 
maximum. 
For a particular parameter (AUC0-t , Cmax , ANC_Emax,  ANC Tmax, AUECCD34+, AUECCD34+ 0-
∞CD34+_Emax,  CD34+ Tmax  AUC0-∞,  t1/2,  λz, CL, AUECANC, AUECANC 0-∞and Protein-
content corrected AUC0-t, AUC0-∞, and Cmax ) within a particular cohort/cycle, only those 


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 13
subjects who have sufficient data in the cycle to calculate the parameter will be included. 
Sufficient data is defined as having more than 3 measurable values where the parameter can 
be reliably calculated. 
PD/PK variables will be listed with indicator variables for antibody test results ( and anti-
PEG, before and after dosing for each cycle). PD/PK variables will be summarized for FAS 
and FAS excluding subjects who have confirmed positive anti-pegfilgrastim (anti-drug) 
antibody tests.  Data for subjects with positive anti-pegfilgrastim (anti-drug) antibody test 
results and positive anti-PEG antibody test results will be listed.  
5.3. Methods to Manage Missing Data
Missing values will not be imputed.  
5.4. Primary Endpoint(s)
Endpoints: 
Cycle 0
PD: AUECANC
PK: AUC0-∞and Cmax
Analysis population for PD/PK parameters: FAS and FAS excluding subjects with positive 
anti-pegfilgrastim (anti-drug) antibody test results.
These PD/PK parameters will be summarized by cohort (Cohort 1 and 2) using descriptive 
statistics.
Cycles 1-4
PD: DSN in Cycle 1.
PK: AUC0-t and Cmax in Cycle 1 and Cycle 4. 
Analysis population for PD/PK parameters: FAS and FAS excluding subjects with positive 
anti-pegfilgrastim (anti-drug) antibody test results.
These PD/PK parameters will be summarized by cycle within Cohort 3 using descriptive 
statistics.
5.5. Secondary Endpoint
Endpoints: 
Cycle 0
PD: 

ANC_Emax, ANC Tmax, AUECANC 0-∞.


PF-06881894 C1221002/ZIN-130-1504
Statistical Analysis Plan Amendment 1
Page 14

AUECCD34+ 0-t, CD34+_Emax, CD34+ Tmax, AUECCD34+ 0-∞.
PK: AUC0-t, Cmax, Tmax, t1/2, λz, CL, protein-content corrected AUC0-t,  AUC0-∞,  and Cmax.
Analysis population for PD/PK parameters: FAS and FAS excluding subjects with positive 
anti-pegfilgrastim (anti-drug) antibody test results.
These PD/PK parameters will be summarized by cohort (Cohorts 1 and 2) using descriptive 
statistics.
Cycle 1-4
PD: 

DSN in Cycle 4.

ANC nadir, time of ANC nadir, AUECANC, incidence of FN, incidence of severe 
neutropenia , time to ANC recovery, and AUECANC 0-∞in Cycle 1 and Cycle 4.
PK: AUC0-∞, Tmax, t1/2, λz, CL, protein-content corrected AUC0-t,  AUC0-∞,  and Cmax in 
Cycle 1 and Cycle 4. 
Analysis population for PD/PK parameters: FAS and FAS excluding subjects with positive 
anti-pegfilgrastim (anti-drug) antibody test results.
These PD/PK parameters will be summarized by cycle within Cohort 3 using descriptive 
statistics.
5.6. Other Endpoint(s)
PF-06881894 (HSP-130) concentration and CD34+ values will be summarized by cycle 
within cohorts using descriptive statistics.
Analysis population: FAS and FAS excluding subjects with positive anti-pegfilgrastim (anti-
drug) antibody test results
5.7. Subset Analyses 
Not planned.
5.8. Baseline Summaries
Summaries of baseline characteristics (demography, medical history, previous medication 
use) will follow Pfizer’s implementation of CDISC standards; these will be presented by 
cohort.


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5.9. Safety Summaries and Analyses
Safety (adverse events, serious adverse events, discontinuations from study, vital signs, 
ECGs, concomitant medication use) and treatment exposure will be summarized by cohort
according to Pfizer’s implementation of CDISC standards for safety reporting.
Adverse events for subjects with positive anti-pegfilgrastim and positive anti-PEG antibody 
test results will be listed together with antibody test information. 
Quantitative laboratory test measurements and change from baseline will be summarized by
cycle within cohorts.  All laboratory values outside the normal range will be flagged in the 
data listing. NCI CTCAE information will be listed.
Quantitative vital sign variables will be listed and change from baseline will be summarized 
by cycle within cohorts. 
ECG, physical exam, immunogenicity, WHO Performance Status, Clinical Index of Stable 
Febrile Neutropenia (CISNE), and quality of life assessment FACT-N data will be listed.
Immunogenicity data will be summarized and listed. 
6. INTERIM ANALYSES
Not applicable.