Conditions: Metastatic Breast Cancer Locally Recurrent Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 432
Healthy volunteers: no

Brief summary:
This is a phase 3, multicenter, open-label, randomized active-controlled, parallel group to investigate the efficacy, safety and tolerability of intravenous balixafortide given with eribulin versus eribulin alone in the treatment of HER2 negative, Locally Recurrent or Metastatic Breast Cancer.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Eribulin intervention 2: Balixafortide
Intervention descriptions: intervention 1: Eribulin alone intervention 2: Balixafortide + Eribulin

Protocol document:
Prot_000.pdf: 
Sponsor Logo/Name: Polyphor Ltd 
Date: 15 July 2019  
Protocol No.: POL6326-009 
Version 3.0 
  
CONFIDENTIAL 
Page 1 of 155 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
CONFIDENTIAL 
Protocol No: 
POL6326-009 
IND No: 
118.448 
EudraCT No: 
2018-004211-42 
Title: 
An International, Phase 3, Multicenter, Randomized, Open-
Label Trial Comparing Balixafortide in combination with 
Eribulin versus Eribulin alone in Patients with HER2 negative, 
Locally Recurrent or Metastatic Breast Cancer (FORTRESS)   
Development Phase: 
Phase 3 
Sponsor: 
Polyphor Ltd Hegenheimermattweg 125, CH-4123 Allschwil, 
Switzerland  
Co-ordinating 
Investigators: 
 
Javier Cortés Castán, MD, PhD 
IOB Institute of Oncology, Madrid & Barcelona 
Ruber International Hospital 
Calle de La Maso 38 
28034 Madrid, Spain 
 
Peter A. Kaufmann, MD 
Breast Oncology, Division of Hematology/Oncology 
University of Vermont Cancer Center 
05405 Burlington, VT, USA 
 
 
Protocol Version and Date: 
Final Protocol Version 3.0 Date: 15 July 2019  
 
 
Confidential 
This document is the property of Polyphor Ltd, Allschwil, Switzerland. It is intended for restricted use 
only and may not─in full or part─be passed on, reproduced, published or used without express 
permission of Polyphor Ltd All rights reserved. 
 
 
 
 
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Date: 15 July 2019  
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Version 3.0 
  
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Page 2 of 155 
PROTOCOL VERSIONS HISTORY 
The table below is intended to capture study protocol versions history, including a description 
of the change and rationale.  
 
Version Date 
Amend-
ment 
Number 
Description of Change  
Brief 
Rationale/Comment 
Draft 
1.0 
28 
September 
2018 
 
This is the first version.  
 
Not signed by Sponsor 
and not submitted to 
regulatory authorities  
 
Draft 
1.1 
11 
October 
2018 
 
Frequency of bone scans 
changed.   
Some assessments for 30-
Day Safety Follow-up 
removed. 
Further information added to 
Section 3.2 on justification for 
dose of balixafortide. 
Editorial amendments made.  
Improving clarity and 
practicality of 
information/Sent to FDA 
for type B meeting  
Final 
2.0 
29 
November 
2018 
 
Additional assessments for 
End-of-Treatment evaluation. 
Primary Objective, efficacy 
endpoints, and statistical 
section amended. 
Nomenclature for populations 
to be studied amended. 
Guidance on contraception 
amended for inclusion criteria 
and elsewhere in protocol. 
Exclusion criteria for drugs 
that prolong the QT interval 
or cause torsades de pointes 
amended. A table of drugs 
known to cause torsades de 
pointes added to Appendix 1.   
Formulation, packaging and 
storage information 
amended. 
Changes made post 
discussion at FDA 
meeting/final and 
signed version to be 
submitted to regulatory 
authorities 
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Date: 15 July 2019  
Protocol No.: POL6326-009 
Version 3.0 
  
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Page 3 of 155 
Version Date 
Amend-
ment 
Number 
Description of Change  
Brief 
Rationale/Comment 
Guidance provided on 
management of AESIs and 
AEPIs.   
Editorial amendments. 
Changes to administration of 
the trial. 
Final 
3.0 
15 
July 
2019 
1 
Number 
of 
study 
visits 
reduced 
for 
eribulin 
monotherapy treatment arm. 
PK 
and 
immunogenicity 
assessments 
no 
longer 
required for these patients. 
To reduce the burden of 
unnecessary 
assessments and visits 
for these patients.  
 
 
 
Separate schedules provided 
for each treatment arm. 
 
Number of study visits 
reduced 
for 
eribulin 
monotherapy treatment 
arm. 
 
 
 
Assessments 
for 
tumor 
biopsy, 
PK, 
exploratory 
biomarkers, 
and 
immunogenicity 
testing 
integrated 
with 
other 
assessments in Schedules. 
To 
allow 
all 
assessments 
to 
be 
displayed together for 
each treatment arm. 
 
 
 
Number of footnotes reduced 
and 
cross-references 
provided to relevant sections 
of protocol. 
To improve presentation 
of schedules and to 
reduce duplication of 
information. 
 
 
 
Section 
2.4 
updated 
to 
provide information from new 
studies including a 13-week 
repeat dose toxicity study in 
cynomolgus 
monkeys, 
studies 
investigating 
the 
immunogenicity 
and 
phototoxicity of balixafortide, 
and studies investigating the 
effects of balixafortide on 
cardiac ion channels.  
To provide the latest 
information 
from 
non-clinical studies. 
 
 
 
Included 
updated 
survival 
data from POL6326-007 study 
in Section 2.5.1.  
Included 
information 
on 
effects of balixafortide on 
To provide up-to-date 
survival information. 
 
To 
explain 
whether 
there is potential for a 
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Version 3.0 
  
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Page 4 of 155 
Version Date 
Amend-
ment 
Number 
Description of Change  
Brief 
Rationale/Comment 
eribulin pharmacokinetics and 
vice versa in Section 2.5.1.  
drug 
interaction 
between eribulin and 
balixafortide. 
 
 
 
New 
Subsection 
2.5.2 
included.  
To 
summarise 
balixafortide population 
pharmacokinetics. 
 
 
 
Additional information added 
to Section 3.2. 
To provide justification 
for the balixafortide + 
eribulin dose regimen in 
terms of disruption of 
the 
tumor 
microenvironment.  
 
 
 
Included 
statement 
on 
hormonal 
contraception 
in 
Section 5.4.5. 
To clarify which women 
can 
take 
hormonal 
contraception. 
 
 
 
Provided 
additional 
information on dosing delays 
and 
interruptions 
in 
Section 6.1.2.1. 
To 
provide 
practical 
information on action to 
take in these situations. 
 
 
 
Treatment Period in Section 7 
separated by treatment arm. 
 
Assessments in Section 7 
arranged in relation to timing 
of 
study 
medication 
administration.   
Number of study visits 
reduced 
for 
eribulin 
monotherapy treatment 
arm. 
To allow information to 
be used in a practical 
way. 
 
 
 
Rationalized 
visits 
for 
exploratory biomarkers in all 
patients. 
To accommodate the 
reduced visits in the 
eribulin 
monotherapy 
treatment arm. 
 
 
 
Tabulated 
information 
on 
visits 
and 
timepoints 
for 
assessments of ECG (Section 
9.8), PK (Section 10), and 
Exploratory 
Biomarkers 
(Section 11.2.2).  
To improve presentation 
and usability. 
 
 
 
Changes to administration of 
the trial 
New Chief Medical 
Officer and 
Development Officer 
from Polyphor Ltd. 
 
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Sponsor Logo/Name: Polyphor Ltd 
Protocol No.: POL6326-009 
Version 3.0 
PROTOCOL SIGNATURE PAGE 
Protocol Number: POL6326-009 
Version 3.0 Date: 15 July 2019 
Date: 15 July 2019 
Protocol Title: An International, Phase 3, Multicenter, Randomized, Open-Label Trial 
Comparing Balixafortide in combination with Eribulin versus Eribulin alone in Patients with 
HER2 negative, Locally Recurrent or Metastatic Breast Cancer (FORTRESS) 
Sponsor Approval 
Signature 
Name, academic degree: Frank Weber, MD 
Function: Chief Medical and Development Officer 
Institution: Polyphor Ltd 
Address: Hegenheimermattweg 125, 
CH-4123 Allschwil, 
Switzerland 
Telephone number: +41 61 567 1600 
Fax number: +41 61 567 1601 
Date 
CONFIDENTIAL 
Page 5 of 155 
147


Sponsor Logo/Name: Polyphor Ltd 
Protocol No.: POL6326-009 
Version 3.0 
Co-ordinating Investigators 
Date: 15 July 2019 
I agree to conduct the clinical trial in accordance with this clinical trial protocol and in 
compliance with Good Clinical Practice and all applicable regulatory requirements. 
Signature 
Date: 
Name, academic degree: Javier Cortes Castan, MD, PhD 
Institution: IOB Institute of Oncology, Madrid & Barcelona, Ruber International Hospital 
Address: Calle de La Maso 38 
28034 Madrid, Spain 
Telephone number: +34 91 336 82 63 
CONFIDENTIAL 
Page 6 of 155 
148


Sponsor Logo/Name: Polyphor Ltd 
Protocol No.: POL6326-009 
Version 3.0 
Co-ordinating Investigators 
Date: 15 July 2019 
I agree to conduct the clinical trial in accordance with this clinical trial protocol and in 
compliance with Good Clinical Practice and all applicable regulatory requirements. 
~(t;/1~ 
Signature 
Date: 
Name, academic degree: Peter A. Kaufmann, MD 
Institution: University of Vermont Cancer Center 
Address: 05405 Burlington, VT, USA 
Telephone number: 802 847-8400 
CONFIDENTIAL 
Page 7 of 155 
149


Sponsor Logo/Name: Polyphor Ltd 
Date: 15 July 2019  
Protocol No.: POL6326-009 
Version 3.0 
  
CONFIDENTIAL 
Page 8 of 155 
DECLARATION OF INVESTIGATORS  
POLYPHOR Ltd 
Protocol Number: POL6326-009 
EudraCT No: 2018-004211-42 
Version 3.0 Date: 15 July 2019 
Protocol Title: An International, Phase 3, Multicenter, Randomized, Open-Label Trial 
Comparing Balixafortide in combination with Eribulin versus Eribulin alone in Patients with 
HER2 negative, Locally Recurrent or Metastatic Breast Cancer (FORTRESS) 
 
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that: 
 
• 
I understand and will conduct the trial according to the clinical trial protocol including 
any ancillary studies or procedures performed on study patients (other than those 
procedures necessary for the well-being of the patients), any approved protocol 
amendments, ICH Good Clinical Practice (ICH Topic E6 GCP(R2)) and all applicable 
Health Authority requirements and national laws. 
• 
I will not deviate from the clinical trial protocol, except where necessary to prevent 
immediate danger to the subject. 
• 
I explicitly agree to provide direct access to all source document pertinent to 
subject enrolled in the study to the Sponsor, its designee, Institutional Review 
Board or Independent Ethics Committee (IEC/IRB) member and competent 
authorities. 
• 
I have been adequately informed about the development of the investigational 
product to date. I confirm the receipt of updated Investigator’s Brochure. I have 
read this study protocol and agree that it contains all the information required to 
conduct the study. 
• 
I will not enroll the first subject in the study until I have received approval from 
the appropriate IRB/IEC and until all legal and regulatory requirements in my country 
have been fulfilled. 
• 
The study will be conducted in accordance with the moral, ethical, and scientific 
principles governing clinical research as set out in the Declaration of Helsinki and 
its amendments (1), the International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines and applicable regulations and laws. 
• 
I agree to obtain, in the manner described in this protocol, written informed consent 
or surrogate informed consent to participate for all subjects enrolled in this study. 
• 
I will ensure that the study drug(s) supplied by the Sponsor are being used 
only as described in this protocol. 
• 
I am aware of the requirements for the correct reporting of serious adverse events, 
and I commit to document and to report such events as required by Polyphor and in 
accordance with Health Authority Regulatory requirements. 
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Date: 15 July 2019  
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Version 3.0 
  
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• 
I agree to supply – upon request – the Sponsor or Sponsor`s designee with evidence 
of current laboratory accreditation, the name and address of the laboratory, and a 
list of normal values and ranges. 
• 
I agree with the use of results of the study for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals. 
• 
I agree to keep all source documents and case report forms as specified in the 
relevant sections of this protocol. 
• 
I will provide all required Regulatory Authority forms, curriculum vitae of myself and 
sub-investigators before the study starts, which may be submitted to regulatory 
authorities. 
• 
Furthermore, I confirm herewith that the Sponsor is allowed to enter and utilize my 
professional contact details and function in an electronic database for internal 
purposes and for submission to Health Authorities worldwide. 
• 
I agree to supply the Sponsor with any necessary information regarding ownership 
interest and financial ties (including those of my spouse and dependent children), and 
to provide updates as necessary to the Sponsor which will use any such information 
that is collected solely for the purpose for complying with the regulatory requirements 
 
 
 
Investigator Signature                         Date 
 
 
 
Print Name and Title 
 
 
 
Name and Address of Institution 
 
 
 
 
 
 
 
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SPONSOR AND TRIAL ADMINISTRATIVE STRUCTURE 
Name and Address of the Sponsor 
Polyphor Ltd 
Hegenheimermattweg 125 
4123 Allschwil, Switzerland 
  
Contract Research Organization 
PPD Global Ltd 
Granta Park, Great Abington 
Cambridge, CB21 6GQ 
United Kingdom 
 
Medical Monitoring by CRO 
PPD Global Ltd 
Granta Park, Great Abington 
Cambridge, CB21 6GQ 
United Kingdom 
Drug Safety Officer 
PPD PVG EMEA fax: +44 1223 374 102 
PPD PVG EMEA email: EMEAAsiaSafetyCentral.SM@ppdi.com 
PPD PVG EMEA hotline: +44 1223 374 240 
 
 
 
 
 
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TABLE OF CONTENTS  
PROTOCOL VERSIONS HISTORY ............................................................................ 2 
TABLE OF CONTENTS ............................................................................................ 11 
LIST OF TABLES ...................................................................................................... 15 
LIST OF FIGURES .................................................................................................... 16 
ABBREVIATIONS AND DEFINITIONS ..................................................................... 17 
1. 
PROTOCOL SYNOPSIS ........................................................................ 22 
1.1 
Study Schedule .............................................................................................. 32 
1.1.1 
Schedule of Assessments for Balixafortide + Eribulin Treatment Arm ... 32 
1.1.1.1 Screening, Cycle 1, and Cycle 2 ..................................................... 32 
1.1.1.2 Cycle 3, Subsequent Cycles, and Post-treatment Phase ................ 35 
1.1.2 
Schedule of Assessments for Eribulin Monotherapy Treatment Arm ..... 38 
2. 
INTRODUCTION .................................................................................... 41 
2.1 
Background on the Disease to be Treated ..................................................... 41 
2.2 
Balixafortide ................................................................................................... 42 
2.3 
Eribulin ........................................................................................................... 44 
2.4 
Balixafortide Non-Clinical Development Overview ......................................... 44 
2.5 
Balixafortide Overview of Clinical Studies ...................................................... 45 
2.5.1 
Phase 1 Study (POL6326-007 – Ongoing at the time of Protocol 
development) ......................................................................................... 46 
2.5.2 
Balixafortide Population Pharmacokinetics ............................................ 47 
2.6 
Balixafortide Current Benefit/Risk Ratio ......................................................... 47 
2.7 
Conduct of Study ............................................................................................ 48 
3. 
STUDY DESIGN .................................................................................... 48 
3.1 
Scientific Rationale for Study Design ............................................................. 48 
3.2 
Justification for Dose ...................................................................................... 49 
3.3 
Overall Design ................................................................................................ 49 
3.4 
Randomization and Treatment Allocation ....................................................... 52 
4. 
STUDY OBJECTIVES AND ENDPOINTS ............................................. 53 
4.1 
Primary Objective ........................................................................................... 53 
4.2 
Secondary Objectives .................................................................................... 53 
4.3 
Exploratory Objectives ................................................................................... 53 
4.4 
Endpoints ....................................................................................................... 53 
4.4.1 
Overall Population Efficacy Endpoints ................................................... 53 
4.4.2 
3rd Line + Population Efficacy Endpoints................................................ 54 
4.4.3 
Secondary Safety Endpoints .................................................................. 55 
4.4.4 
Exploratory Endpoints ............................................................................ 55 
5. 
STUDY POPULATION ........................................................................... 56 
5.1 
Patient Inclusion Criteria ................................................................................ 56 
5.2 
Patient Exclusion Criteria ............................................................................... 57 
5.3 
Patient Withdrawal Criteria ............................................................................. 58 
5.3.1 
Discontinuation from Treatment ............................................................. 58 
5.3.2 
Discontinuation from Study .................................................................... 58 
5.3.3 
Patient Withdrawing Consent ................................................................. 59 
5.3.4 
Patient Withdrawal in case of Pregnancy ............................................... 59 
5.3.5 
Patient Replacement .............................................................................. 59 
5.4 
Patient Restrictions ........................................................................................ 59 
5.4.1 
Prior or Concomitant Medication ............................................................ 59 
5.4.2 
Permitted Medications ........................................................................... 60 
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5.4.3 
Prohibited Medications ........................................................................... 60 
5.4.4 
Medications Not Recommended ............................................................ 61 
5.4.5 
Women and Men of Childbearing Potential ............................................ 61 
5.4.5.1 Pregnancy Test ............................................................................... 62 
6. 
STUDY MEDICATION ............................................................................ 62 
6.1 
Study Drug Administration .............................................................................. 62 
6.1.1 
Dosing and Administration ..................................................................... 62 
6.1.2 
Dose Modifications (including delays and interruptions) ........................ 63 
6.1.2.1 Dosing Delays or Interruptions ........................................................ 64 
6.2 
Preparation/Handling/Storage/Accountability ................................................. 66 
6.2.1 
Accountability ......................................................................................... 66 
6.2.2 
Formulation, Appearance, Packaging, and Labelling ............................. 66 
6.2.3 
Product Storage and Stability ................................................................ 66 
6.2.4 
Preparation ............................................................................................ 67 
6.3 
Assessment of Compliance ............................................................................ 67 
7. 
STUDY ASSESSMENTS AND PROCEDURES .................................... 67 
7.1 
Screening Visit (Day –21 to –1) ...................................................................... 68 
7.2 
Randomization ............................................................................................... 69 
7.3 
Treatment Period─Balixafortide + Eribulin Treatment Arm Only .................... 69 
7.3.1 
Cycle 1 ................................................................................................... 69 
7.3.1.1 Cycle 1 Day 1 .................................................................................. 69 
7.3.1.2 Cycle 1 Day 2 .................................................................................. 70 
7.3.1.3 Cycle 1 Day 3 .................................................................................. 71 
7.3.1.4 Cycle 1 Day 8 .................................................................................. 71 
7.3.1.5 Cycle 1 Day 9 .................................................................................. 72 
7.3.1.6 Cycle 1 Day 10 ................................................................................ 72 
7.3.2 
Subsequent Cycles ................................................................................ 72 
7.3.2.1 Day 1 ............................................................................................... 72 
7.3.2.2 Day 2 ............................................................................................... 73 
7.3.2.3 Day 3 ............................................................................................... 74 
7.3.2.4 Day 4 (Cycle 3 only) ........................................................................ 74 
7.3.2.5 Day 5 (Cycle 3 only) ........................................................................ 74 
7.3.2.6 Day 8 ............................................................................................... 75 
7.3.2.7 Day 9 ............................................................................................... 75 
7.3.2.8 Day 10 ............................................................................................. 76 
7.3.2.9 Day 21 ............................................................................................. 76 
7.4 
Treatment Period─Eribulin Monotherapy Treatment Arm Only ...................... 76 
7.4.1 
Cycle 1 ................................................................................................... 76 
7.4.1.1 Cycle 1 Day 2 .................................................................................. 76 
7.4.1.2 Cycle 1 Day 9 .................................................................................. 77 
7.4.2 
Subsequent Cycles ................................................................................ 77 
7.4.2.1 Day 2 ............................................................................................... 77 
7.4.2.2 Day 9 ............................................................................................... 78 
7.4.2.3 Day 21 ............................................................................................. 79 
7.5 
Unscheduled Visit........................................................................................... 79 
7.6 
End of Treatment Visit .................................................................................... 79 
7.7 
30-Day Safety Follow-up ................................................................................ 80 
7.8 
Long-term Follow-up ...................................................................................... 80 
7.8.1 
PD Follow-up ......................................................................................... 80 
7.8.2 
Survival Follow-up.................................................................................. 80 
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7.9 
Duration of Study Participation ....................................................................... 81 
7.10 
End of Study Definition ................................................................................... 81 
8. 
ASSESSMENT OF EFFICACY .............................................................. 81 
8.1 
Independent Review of Disease Response .................................................... 81 
8.2 
Tumor Assessments ....................................................................................... 82 
8.2.1 
Screening or Baseline Tumor Assessment ............................................ 82 
8.2.2 
Post-baseline Tumor Assessments........................................................ 82 
8.2.3 
Further Information for CT/MRI Scans ................................................... 86 
8.3 
Efficacy Parameters ....................................................................................... 86 
8.3.1 
Progression Free Survival ...................................................................... 87 
8.3.2 
Overall Survival ...................................................................................... 87 
8.3.3 
Objective Response Rate ...................................................................... 87 
8.3.4 
Time to Response .................................................................................. 87 
8.3.5 
Duration of Response ............................................................................ 87 
8.3.6 
Clinical Benefit Rate............................................................................... 87 
8.3.7 
Disease Control Rate ............................................................................. 87 
9. 
ASSESSMENT OF SAFETY .................................................................. 87 
9.1 
Safety Assessments ....................................................................................... 87 
9.2 
Adverse Events .............................................................................................. 90 
9.2.1 
Adverse Event Definition ........................................................................ 90 
9.2.2 
Serious Adverse Events ......................................................................... 91 
9.2.3 
Severity Assessment ............................................................................. 92 
9.2.4 
Causality Assessment ............................................................................ 92 
9.2.5 
Reporting Requirements ........................................................................ 93 
9.2.5.1 Serious Adverse Event Reporting ................................................... 93 
9.2.5.2 Non-Serious Adverse Event Reporting ........................................... 93 
9.2.5.3 Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators ............ 94 
9.2.6 
Monitoring and Management of AESIs and AEPIs ................................ 94 
9.2.6.1 Potential Cases of Drug-induced Liver Injury .................................. 94 
9.2.6.2 QT Prolongation .............................................................................. 95 
9.2.6.3 Infusion-Related Reactions ............................................................. 96 
9.2.6.4 Neutropenia .................................................................................... 96 
9.2.6.5 Thrombocytopenia .......................................................................... 98 
9.2.6.6 Peripheral Neuropathy .................................................................... 98 
9.2.6.7 Renal Impairment ............................................................................ 98 
9.3 
Exposure During Pregnancy .......................................................................... 98 
9.4 
Medication Errors ........................................................................................... 99 
9.5 
Occupational Exposure .................................................................................. 99 
9.6 
Physical Examination ..................................................................................... 99 
9.7 
Vital Signs .................................................................................................... 100 
9.8 
12 Lead Electrocardiogram .......................................................................... 101 
9.9 
Clinical Laboratory Evaluations .................................................................... 102 
10. 
PHARMACOKINETIC ASSESSMENT ................................................. 102 
10.1 
Balixafortide + Eribulin treatment arm .......................................................... 103 
11. 
EXPLORATORY ASSESSMENTS....................................................... 104 
11.1 
Immunogenicity Assessment ........................................................................ 104 
11.2 
Exploratory Biomarkers Assessment ............................................................ 105 
11.2.1 Tumor Tissue ....................................................................................... 105 
11.2.2 Biomarkers in Blood or Plasma ............................................................ 106 
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11.3 
Patient Reported Outcomes ......................................................................... 108 
12. 
STATISTICS ........................................................................................ 109 
12.1 
General Statistical Methods ......................................................................... 109 
12.2 
Overall Population Efficacy Analysis Plan relevant to the EU and other 
jurisdictions in which the 2nd line + Eribulin Label applies ............................. 110 
12.2.1 Sample Size ......................................................................................... 110 
12.2.2 Analysis Sets ....................................................................................... 110 
12.2.3 Demographics and other Baseline Characteristics .............................. 110 
12.2.3.1 Medical History.............................................................................. 111 
12.2.3.2 Medical History of Prior Systemic Cancer/Oncology Therapies .... 111 
12.2.3.3 Previous Radiotherapy and Surgical History ................................. 111 
12.2.4 Patient Disposition ............................................................................... 111 
12.2.5 Protocol Deviations .............................................................................. 112 
12.2.6 Treatments and Medication ................................................................. 112 
12.2.6.1 Prior and Concomitant Medication ................................................ 112 
12.2.6.2 Subsequent Anti-cancer Therapy .................................................. 112 
12.2.6.3 Exposure/Study Medication .......................................................... 112 
12.2.7 Efficacy Analyses ................................................................................. 113 
12.2.7.1 Primary Endpoint: Progression Free Survival ............................... 113 
12.2.7.2 Key Secondary Endpoint: Overall survival .................................... 113 
12.2.7.3 Type I Error Control ....................................................................... 113 
12.2.7.4 Other Secondary Endpoints .......................................................... 114 
12.2.7.5 Exploratory Efficacy Endpoints...................................................... 115 
12.3 
3rd line + Population Efficacy Analysis Plan relevant to the US and other 
jurisdictions in which the 3rd line + Eribulin Label applies ............................. 115 
12.3.1 Sample Size ......................................................................................... 115 
12.3.2 Analyses Sets ...................................................................................... 115 
12.3.2.1 3rd line + Population ....................................................................... 115 
12.3.3 Demographics and Other Baseline Characteristics ............................. 116 
12.3.3.1 Medical History.............................................................................. 116 
12.3.3.2 Medical History of Prior Systemic Cancer/Oncology Therapies .... 116 
12.3.3.3 Previous Radiotherapy and Surgical History ................................. 116 
12.3.4 Patient disposition ................................................................................ 116 
12.3.5 Protocol Deviations .............................................................................. 116 
12.3.6 Treatments and Medication ................................................................. 117 
12.3.6.1 Prior and Concomitant Medication ................................................ 117 
12.3.6.2 Subsequent Anti-cancer Therapy .................................................. 117 
12.3.6.3 Exposure/Study Medication .......................................................... 117 
12.3.7 Efficacy Analyses ................................................................................. 117 
12.3.7.1 Co-Primary Endpoints: Objective Response Rate and Progression 
Free Survival ................................................................................. 117 
12.3.7.2 Key Secondary Endpoint: Overall survival .................................... 117 
12.3.7.3 Type I Error Control ....................................................................... 117 
12.3.7.4 Other Secondary Endpoints .......................................................... 120 
12.3.7.5 Exploratory Efficacy Endpoints...................................................... 120 
12.4 
Safety Analysis ............................................................................................. 120 
12.4.1 Adverse Events .................................................................................... 120 
12.4.2 Laboratory Results ............................................................................... 120 
12.4.3 Analysis of Vital Signs .......................................................................... 121 
12.4.4 Physical Examination ........................................................................... 121 
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12.4.5 12-Lead Electrocardiogram .................................................................. 121 
12.4.6 Exposure During Pregnancy ................................................................ 121 
12.5 
Deviations from the Original Statistical Plan ................................................. 121 
12.6 
Data Management ........................................................................................ 121 
12.7 
Data Safety Monitoring Committee ............................................................... 122 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................... 122 
13.1 
Source Data ................................................................................................. 122 
13.2 
Source Documents ....................................................................................... 122 
13.3 
Direct Access ............................................................................................... 122 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................... 123 
14.1 
Quality Control.............................................................................................. 123 
14.2 
Quality Assurance ........................................................................................ 123 
14.2.1 Inspection ............................................................................................ 123 
14.2.2 Audit ..................................................................................................... 123 
15. 
ETHICS ................................................................................................ 123 
15.1 
Independent Ethics Committee/Institutional Review Board Approval ........... 123 
15.2 
Informed Consent ......................................................................................... 124 
15.3 
Modification of Protocol ................................................................................ 125 
15.4 
Safety Reporting........................................................................................... 125 
15.5 
Trial Termination .......................................................................................... 126 
15.6 
End of Trial Notification and Submission of Summary Report ...................... 126 
16. 
DATA HANDLING AND RECORD KEEPING ...................................... 126 
16.1 
Completion of Electronic Case Report Forms .............................................. 126 
16.2 
Confidentiality ............................................................................................... 126 
16.3 
Archiving and Retention of Investigational Records ..................................... 127 
17. 
FINANCING AND INSURANCE ........................................................... 128 
18. 
PUBLICATION POLICY ....................................................................... 128 
19. 
REFERENCES ..................................................................................... 129 
20. 
APPENDICES ...................................................................................... 133 
Appendix 1 Prohibited Medications ......................................................................... 133 
Appendix 2 ECOG Performance Status .................................................................. 135 
Appendix 3 Summary of RECIST v1.1 Guidelines .................................................. 136 
Appendix 4 Summary of iRECIST Guidelines ......................................................... 143 
Appendix 5 Scales and Assessments ..................................................................... 149 
Appendix 6 Prescribing Information and Labels for Eribulin .................................... 150 
Appendix 7 ASCO Guidance on the Use of CSFs ................................................... 151 
Appendix 8 ASCO Guidance on Outpatient Management of Fever and Neutropenia in 
Patients Treated for Malignancy ................................................................... 152 
Appendix 9 ASCO Guidance on Platelet Transfusions for Patients with Cancer ..... 153 
Appendix 10 Any Additional Study Information that the Patient will Receive ........... 154 
Appendix 11 Quality of Life Patient Questionnaires ................................................ 155 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments for Balixafortide + Eribulin Treatment Arm: 
Screening, Cycle 1, and Cycle 2 .............................................................. 32 
Table 2 
Schedule of Assessments for Balixafortide + Eribulin Treatment Arm: Cycle 
3, Subsequent Cycles, and Post-treatment Phase ................................... 35 
Table 3 
Schedule of Assessments for Eribulin Monotherapy Treatment Arm ....... 38 
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Table 4 
Recommended dose reductions for eribulin ............................................. 64 
Table 5 
Determination of Objective Tumor Response for Target Lesions ............. 83 
Table 6 
Determination of Tumor Response for Non-target Lesions ...................... 84 
Table 7 
Determination of Overall Response at each Timepoint specified in the Study 
Schedule for Patients with Measurable Disease at Baseline .................... 84 
Table 8 
Determination of Overall Response at each Timepoint specified in the Study 
Schedule for Patients with Non-measurable Disease at Baseline ............ 85 
Table 9 
AEs of Particular Interest and AEs of Special Interest .............................. 89 
Table 10 Patient Risk Factors for Febrile Neutropenia ............................................ 97 
Table 11 ECG Schedule ........................................................................................ 101 
Table 12 Schedule for Pharmacokinetic Assessments of All Patients in the 
Balixafortide + Eribulin Treatment Arm ................................................... 103 
Table 13 Schedule for Pharmacokinetic Assessments of Patients at Selected Sites in 
the Balixafortide + Eribulin Treatment Arm ............................................. 104 
Table 14 Schedule for Immunogenicity Assessments for Patients on the Balixafortide 
+ Eribulin Treatment Arm ....................................................................... 104 
Table 15 Schedule for Blood Exploratory Biomarker Assessment of All Patients in the 
Balixafortide + Eribulin Treatment Arm ................................................... 106 
Table 16 Schedule for Blood Exploratory Biomarker Assessment of All Patients in the 
Eribulin Monotherapy Treatment Arm ..................................................... 107 
Table 17 Best overall response when confirmation of CR and PR required .......... 140 
Table 18 Key Principles to Consider ..................................................................... 145 
Table 19 Assignment of Timepoint Response Using iRECIST .............................. 146 
 
LIST OF FIGURES 
Figure 1 
Downstream signaling pathways linked with SDF-1/CXCR4 signaling ..... 42 
Figure 2 
Type I Error Control for Primary and Secondary Efficacy Analyses in the 
Overall Population .................................................................................. 114 
Figure 3 
Type I Error Control for Primary and Secondary Efficacy Analyses in the 
3rd line + (3rd to 5th line of therapy) Population ....................................... 119 
 
 
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ABBREVIATIONS AND DEFINITIONS 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AEPI 
AE of Particular Interest 
AESI 
AE of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase  
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase  
ATC 
Anatomical, Therapeutic, or Chemical 
AUC 
Area Under the Curve 
BC 
Breast Cancer 
β-HCG 
Beta Human Chorionic Gonadotropin 
BMA 
Bone-Modifying Agent 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBR 
Clinical Benefit Rate 
CD34+ 
Cluster of Differentiation 34+ 
CDK 
Cyclin-Dependent Kinase 
CI 
Confidence Interval 
CISH 
Chromogenic In Situ Hybridization 
CK 
Creatine Kinase 
CL 
Clearance 
Cmax 
Maximum Concentration 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSF 
Colony Stimulating Factor 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXCR4 
C-X-C Chemokine Receptor Type 4 
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CYP 
Cytochrome P 
D 
Day 
DCR 
Disease Control Rate 
DNA 
Deoxyribonucleic acid  
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eDISH 
evaluation of Drug-induced Serious Hepatotoxicity 
EORTC-QLQ-
C30 
European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 
EoT 
End-of-Treatment 
EQ-5D 
EuroQol-5D 
EQ VAS 
EQ Visual Analogue Scale 
ER 
Estrogen Receptor 
ER+ 
Estrogenic-receptor Positive 
ER- 
Estrogenic-receptor Negative 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FACT-B 
Functional Assessment of Cancer Therapy Breast 
FDA 
Food and Drug Administration (US) 
FDG-PET 
18-fluoro-deoxyglucose Positron Emission Tomography 
FISH 
Fluorescence in Situ Hybridization 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transferase 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HER2 
Human Epidermal Growth Factor Receptor 2 
hERG 
Human ether-a-go-go-related gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Hormone Receptor 
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Ht 
Hematocrit 
iBOR 
Immune Best Overall Response  
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
iCPD 
Immune Confirmed Progressive Disease 
iCR 
Immune Complete Response 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IFN 
Interferon 
IMP 
Investigational Medicinal Product  
INR 
International Normalized Ratio 
iPR 
Immune Partial Response 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
Infusion-Related Reaction 
IRT 
Interactive Response Technology 
iSD 
Immune Stable Disease 
ISF 
Investigator Site File 
ITT 
Intention-To-Treat 
IUD 
Intrauterine Device 
iUPD 
Immune Unconfirmed Progressive Disease 
IWRS 
Interactive Web Response System 
IV 
Intravenous(ly) 
K 
Potassium 
KIM-1 
Kidney Injury Molecule-1 
KR 
Known Risk 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Magnesium 
MRGPRX2 
mas-related gene X2 receptor 
MRI 
Magnetic Resonance Imaging 
msec 
Milliseconds 
Na 
Sodium 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
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NGAL 
Neutrophil Gelatinase-associated Lipocalin 
NOAEL 
No-observed Adverse-effect Level  
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PgR 
Progesterone Receptor 
Ph. Eur. 
European Pharmacopoeia 
PK 
Pharmacokinetic 
PR 
Partial Response 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
QA 
Quality Assurance 
QoL 
Quality of Life 
QTc 
Corrected QT Interval 
QTcF 
QT Interval corrected with Fridericia's formula 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Stable Disease 
SDF-1 
Stromal Cell-Derived Factor-1 
SmPC 
Summary of Product Characteristics 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
t1/2 
Terminal Half-life 
TdP 
Torsades de Pointes 
TEAE 
Treatment Emergent Adverse Event 
UK 
United Kingdom 
US 
United States 
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ULN 
Upper Limit of Normal 
Vz 
Total Volume of Distribution 
WBC 
White Blood Cell 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 
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1. 
PROTOCOL SYNOPSIS 
Protocol number: POL6326-009 
Trial drug: Balixafortide 
Title of the trial: An International, Phase 3, Multicenter, Randomized, Open-Label Trial 
Comparing Balixafortide in combination with Eribulin versus Eribulin alone in Patients with 
HER2 negative, Locally Recurrent or Metastatic Breast Cancer (FORTRESS) 
Sponsor: Polyphor Ltd  
Development Phase: Phase 3 
Study centers:  
This study will be performed in at least 95 centers and 14 countries globally.  
Study period (planned): 
To generate the required number of progression free survival (PFS) events for the main 
analysis, a 12-month recruitment period is anticipated with an expected follow-up period of 
12-months after the last patient is randomized. Patients will then be followed for one 
additional year for overall survival (OS). The study is planned to begin during the first quarter 
of 2019. 
Patient Population: Patients with human epidermal growth factor receptor 2 (HER2) negative, 
locally recurrent or metastatic breast cancer (BC) that has previously been treated with 1−4 
chemotherapeutic regimens for locally recurrent or metastatic BC. Unless contra-indicated for 
safety reasons, patients will have previously received an anthracycline and a taxane in either 
the adjuvant or metastatic setting. In this protocol, locally recurrent BC is defined as 
unresectable locoregionally recurrent BC. 
Two populations of patients will be studied, the: 
• 
Overall Population, who receive study medication as 2nd to 5th line of therapy, which 
will constitute the primary population for regulatory submissions in the European 
Union (EU) and jurisdictions in which the 2nd line + eribulin label applies. 
• 
3rd line + population, who receive study medication as 3rd to 5th line of therapy 
(3rd line +), which will constitute the primary population for regulatory submissions in 
the United States (US) and jurisdictions in which the 3rd line + eribulin label applies. 
 
Study Design:  
In this international, multicenter, open-label, randomized, two-arm, pivotal Phase 3 study, 
eligible patients will be randomly assigned in a 1:1 ratio to one of the following treatment 
regimens: 
Balixafortide + eribulin treatment arm 
or 
Eribulin treatment arm 
 
Cross-over will not be allowed at any time after randomization. 
Patients will be stratified according to: 
• 
Line of therapy (2nd line versus 3rd line +) for locally recurrent or metastatic BC.  
• 
Hormone receptor (HR) status (positive versus negative) based on estrogen receptor 
(ER) or progesterone receptor (PgR) status. 
• 
Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment received previously (received a 
CDK 4/6 inhibitor previously versus not received a CDK 4/6 inhibitor previously). 
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• 
Visceral versus non-visceral disease. Visceral metastases will include brain, pulmonary, 
pleural, hepatic and peritoneal involvement (including pleural effusions and ascites). 
Any other sites of metastases (e.g. bone, lymph nodes, and skin) will be considered to 
be non-visceral. Patients with visceral metastases, irrespective of the presence of any 
other metastatic sites (e.g. bone), will be categorized as visceral. All other patients 
without visceral metastases will be categorized as non-visceral. 
 
Patients will undergo assessment for efficacy, safety and tolerability, pharmacokinetics (PK; 
including metabolites), immunogenicity, Quality of Life (QoL), and exploratory biomarkers 
(including interferon [IFN]-gamma and other circulating cytokines). At selected sites, the study 
will include assessment of additional exploratory blood and tissue biomarkers. 
The Study Schedule of Assessments and sampling are outlined in Section 1.1. 
 
The study will consist of the following:  
• 
Screening Assessments: To be obtained ≤21 days prior to randomization. 
• 
Randomization: Patients will be randomized within 21 days of starting screening and 
after having completed the required screening assessments. Patients will be 
randomized either to the balixafortide + eribulin treatment arm or to the eribulin 
treatment arm. All patients must begin treatment within 3 days after randomization.  
• 
Treatment Phase: Patients will receive 21-day cycles of treatment. All patients will 
receive eribulin on Days 2 and 9 of each cycle (the rational for this frequency is 
explained in Section 3.2). In addition, patients randomized to the balixafortide + eribulin 
arm will receive balixafortide on Days 1−3 and Days 8−10 of each cycle.   
 
Response Assessments During Treatment: From the date of randomization, patients 
will be evaluated according to Response Evaluation Criteria In Solid Tumors (RECIST) 
v1.1 for complete response (CR), partial response (PR), stable disease (SD), or 
progressive disease (PD) based on computed tomography/magnetic resonance 
imaging (CT/MRI) scans performed every 6 weeks (±7 days) during the first year, and 
then performed every 12 weeks (±7 days), thereafter, until PD is documented by 
RECIST v1.1. At the discretion of the Investigator, additional radiographic tumor 
assessments may be done at any time if there is clinical suspicion of disease 
progression.  
 
From the date of randomization, additional bone scans will be performed at the 
discretion of the Investigator (e.g. to confirm CR or if [based on signs and symptoms] 
new bone metastases are suspected).  
 
Following initial documentation of an objective response, a confirmatory CT/MRI scan 
will be performed at least 4 weeks later.  
 
Patients will continue treatment as assigned at randomization, until objective PD 
(according to RECIST v1.1) is documented, there is unacceptable toxicity, death occurs, 
the patient withdraws consent, or the patient is lost to follow-up (whichever occurs first). 
Patients discontinued from treatment, for reasons other than PD, will enter the PD 
Follow-up (as described in PD Follow-up below) unless death occurs, the patient 
withdraws consent to efficacy follow-up, or the patient is lost to follow-up.   
 
• 
End-of-Treatment (EoT) Evaluation: This will occur as soon as possible, within 7 days 
after discontinuation of study medication and prior to initiation of any new anti-cancer 
therapy, regardless of the reason for discontinuation. A targeted physical examination 
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will be conducted. Weight, Eastern Cooperative Oncology Group (ECOG) performance 
status, adverse events (AEs), vital signs, clinical laboratory tests, 12-lead 
electrocardiogram (ECG) and concomitant medications will be assessed and recorded 
for all patients at this visit. Patients who are discontinued from study medication for any 
reason, in the absence of objective PD (according to RECIST v1.1), will undergo tumor 
response assessment. For patients at selected sites, an optional tumor biopsy will be 
performed. Patients will complete QoL questionnaires.   
 
• 
30-Day Safety Follow-up: This will occur 30 days (and no later than 37 days) from the 
last dose of study drug. AEs will be assessed and recorded for all patients at this visit. 
Concomitant medications will also be recorded for patients with unresolved AEs. 
 
• 
Long-term Follow-up:  
(i) PD Follow-up: Regardless of treatment arm, patients who are discontinued from 
study medication for any reason in the absence of PD, will undergo repeat imaging 
and tumor response assessments (including CT/MRI scans) every 8 weeks ±7 days 
(every 12 weeks ±7 days if the patient has been on the study for ≥1 year) until PD 
is documented as per RECIST v1.1, or death occurs, or patient is lost to follow-up, 
or the patient withdraws consent (whichever occurs first). If a patient stops study 
medication and begins other anti-cancer therapy before PD is documented, every 
effort should be made to perform tumor evaluation in these patients until disease 
progression.   
(ii)  Survival Follow-up: The Investigator will monitor the patient for OS status every 
6 months (or more frequently) until death, until the patient withdraws consent to 
follow-up for survival, or until the patient is lost to follow-up (whichever occurs first).  
(iii) Every effort should be made to collect and record all anti-cancer medicines that the 
patient receives during Long-term Follow-up in the patient's source data and 
electronic case report form (eCRF) until the end of study.  
Objectives: 
Primary Objective 
• 
To evaluate the efficacy of balixafortide + eribulin versus eribulin monotherapy on (i) 
PFS in the Overall Population and (ii) PFS and objective response rate (ORR) in the 
3rd line + population. 
Secondary Objectives 
• 
To compare the OS between patients in the balixafortide + eribulin treatment arm versus 
eribulin monotherapy treatment arm. 
• 
To compare measures of tumor response between patients in the balixafortide + eribulin 
treatment arm versus eribulin monotherapy treatment arm.  
• 
To evaluate the safety and tolerability of balixafortide + eribulin versus eribulin 
monotherapy. 
Exploratory Objectives 
• 
To determine whether the treatment outcome correlates with baseline ER, PgR, or 
C-X-C chemokine receptor type 4 (CXCR4) expression level.  
• 
To assess tumor tissue and circulating biomarkers and possible association with patient 
treatment outcome. 
• 
To explore immune response as assessed by iRECIST (2017). 
• 
Measurement of plasma concentration of balixafortide and potential metabolites to 
integrate in a population PK model.  
• 
To assess the QoL as reported by patients in the balixafortide + eribulin treatment arm 
versus eribulin monotherapy treatment arm using standard QoL assessments.  
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Number of patients (total and for each treatment arm): 
In the Overall Population, three hundred and eighty-four patients will be enrolled (192 patients 
in the balixafortide + eribulin treatment arm, and 192 patients in the eribulin treatment arm), 
including three hundred and twenty 3rd line + patients with locally recurrent or metastatic BC.  
Enrolment Criteria: 
Inclusion Criteria 
Patients with measurable and non-measurable disease will be eligible for inclusion in this study 
only if all the following criteria are met:  
1. Patients at least 18 years of age (or according to local regulation). 
2. Documented histologically confirmed BC. 
3. Metastatic BC currently of stage IV disease by American Joint Committee on Cancer criteria 
or unresectable locoregionally recurrent BC. 
4. Molecular status and prior therapies: 
a) Molecular Status 
Eligible patients are, by their patient records and prior therapy, HER2 negative with 
any ER or PgR status. If a previous record of the HR status is not available, the HR 
status should be tested locally. 
HER2 negative (immunohistochemistry [IHC] 0,1 or fluorescence in situ 
hybridization [FISH] or chromogenic in situ hybridization [CISH] HER2:CEP17 ratio 
< 2.0); HER2 2+ patients should be FISH/CISH negative. 
b) Prior Therapies 
Patients with locally recurrent or metastatic BC who have previously received 1−4 
chemotherapeutic regimens for the treatment of locally recurrent or metastatic BC. 
Unless contra-indicated for safety reasons, prior therapy will have included an 
anthracycline and a taxane in either the adjuvant or metastatic setting. 
Patients with HR positive status (ER+ and/or PgR+) must have been treated with at 
least one line of endocrine therapy and considered by the treating physician not to 
be a candidate for further endocrine therapy. 
5. At least 14 days from the completion of any previous cytotoxic chemotherapy, biological 
therapy, or any other investigational agent at time of initiation of study medication. 
Resolution of chemotherapy and radiation therapy related toxicities to Grade 1 or lower 
severity, except for stable sensory neuropathy Grade 2 or lower and alopecia. 
6. Patients must have proved refractory to the most recent chemotherapy, documented by 
progression on or within six (6) months of therapy. 
7. Females of child bearing potential must be willing and able to use highly effective 
contraception (as described in the protocol) whilst they or their male partners are on this 
study from randomization until 3 months after the last dose of study medication 
(Section 5.4.5). Male patients must commit to using an approved form of birth control 
(including double-barrier contraception [e.g. consistent and correct use of male condom 
with diaphragm or male condom with cervical cap] or sterilization method) whilst on 
treatment and for 3 months after the last dose of study medication (Section 5.4.5). 
8. ECOG performance status of 0-2.  
9. Life expectancy of 3 months or more as per Investigator assessment. 
10. Adequate organ function defined at Screening as: 
a) White blood cell (WBC) ≥3000/mm3. 
b) Absolute neutrophil count (ANC) ≥1500/mm3.  
c) Platelets ≥75000/mm3*. 
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d) Creatinine Clearance ≥30 mL/minute as calculated by the Cockcroft-Gault equation 
or serum creatinine <1.5x institutional upper limit of normal (ULN) (2). 
e) Total bilirubin ≤1.5x institutional ULN; aspartate aminotransferase (AST), alanine 
aminotransferase (ALT) ≤3x institutional ULN (for patients with liver metastases, 
≤5x ULN). 
f) Hemoglobin ≥10 g/dL. 
11. Patients who have central nervous system involvement if metastases have been treated 
and are stable for at least 4 weeks after completion of radiation therapy and/or surgery. 
Stable is defined as the absence of the need for dexamethasone or other corticosteroid 
therapy, and radiographic confirmation of SD.  
12. Patients receiving bone-modifying agents (BMA [bisphosphonates or denosumab]) if BMA 
was initiated at least 4 weeks prior to the start of study medication. 
13. Must be willing and able to comply with the protocol and mustunderstand and sign an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent document. 
14. Affiliation with a National Health Insurance plan (applicable to patients in France only). 
 
* ≥100000/mm3 in France 
 
Patient Exclusion Criteria 
Patients will be ineligible if one or more of the following statements are applicable: 
1. Previously received eribulin. 
2. Peripheral neuropathy Grade ≥3. 
3. Receipt of prior CXCR4 therapy. 
4. Receipt of colony stimulating factors (CSFs) filgrastim, pegfilgrastim, or sargramostim 
within 14 days prior to time of initiation of study medication. 
5. Radiation therapy within 14 days prior to time of initiation of study medication. 
6. Severe concurrent illness or psycho-social situation that would limit compliance with 
study requirements or that, in the Investigator’s opinion, would preclude enrolment. 
7. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to balixafortide or eribulin, or known intolerance to balixafortide or eribulin. 
8. Breast feeding or pregnant, as determined by a serum pregnancy test beta human 
chorionic gonadotrophin (β-HCG) at Screening and prior to the administration of study 
medication. 
9. Patients with congestive heart failure, electrolyte abnormalities, bradyarrhythmias, known 
congenital long QT syndrome, QT interval corrected with Fridericia's formula (QTcF) 
≥470 milliseconds (msec) at baseline in the absence of bundle branch block, or currently 
taking drugs at known risk of prolonging the QT interval or causing torsades de pointes 
(TdP) (including Class Ia and III anti-arrhythmic drugs; see also Appendix 1 Prohibited 
Medications). Patients with hypokalemia or hypomagnesemia should not be randomized 
until the hypokalemia or hypomagnesemia is corrected. 
10. Patients with a concurrent malignancy or malignancy 2 years prior to randomization with 
the exception of adequately treated basal and squamous cell carcinoma, non-
melanomatous skin cancer, or curatively resected cervical cancer. 
11. Persons who have been housed in an institution due to a government or judicial order 
(applicable to Germany only). 
Study Medication 
The investigational medicinal product (IMP; as defined by EU regulation) in this study is 
balixafortide. The other drug to be used in this study is eribulin. 
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Dose and route of administration: 
Patients will receive 21-day cycles of treatment. Patients will be randomized to one of the 
following treatment regimens: 
 
Balixafortide + eribulin treatment arm 
Eribulin will be administered, at a dose of 1.4 mg/m2 on Days 2 and 9 and balixafortide will be 
administered at a dose of 5.5 mg/kg on Days 1−3 and Days 8−10 of each 21-day cycle. 
 
Cycle Scheme: 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
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1 
2 
3 
treatment break 
8 
9 
10 
treatment break 
Eribulin 
 
2 
treatment break 
9 
treatment break 
 
Eribulin monotherapy treatment arm 
Eribulin will be administered at a dose of 1.4 mg/m2 on Days 2 and 9 of each 21-day cycle. 
 
Cycle Scheme: 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Eribulin 
 
2 
treatment break 
9 
treatment break 
 
Balixafortide will be administered intravenously (IV) over a minimum of 2 hours ±10 minutes; 
however, the infusion time of balixafortide can be increased to a maximum of 3 hours at the 
discretion of the treating physician, for reasons of patient tolerability (i.e. to manage infusion-
related reactions [IRRs]).   
Eribulin will be administered IV over 2 to 5 minutes. In the balixafortide + eribulin treatment 
arm, eribulin will be administered within 45 minutes after the end of the balixafortide infusion. 
Efficacy Assessments:  
All patients will be evaluated for disease response and OS. Response assessments will be 
conducted according to RECIST v1.1 guidelines and include: 
• 
PFS and objective response (as assessed by the Independent Review Committee 
[IRC]. 
• 
PFS and objective response (as assessed by the local Investigator's review). 
 
Follow-up for OS: The Investigator will monitor the patient for OS status until death, until the 
patient withdraws consent for survival follow-up, or until the patient is lost to follow-up 
(whichever occurs first).   
Safety Assessments: 
Safety Assessments will include evaluation of AEs, vital signs (blood pressure, heart rate, 
respiratory rate, and body temperature), renal function, liver function, ECOG performance 
status, ECG and clinical laboratory evaluations (chemistry, hematology). 
AEs of special interest (AESI), based on the emerging AE profile of balixafortide or established 
risks with eribulin therapy, will be followed closely. Safety monitoring for serious adverse event 
(SAEs) will begin after informed consent is given and will continue until 30 days after the last 
dose of study drug. AEs will be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Type, incidence, 
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severity, timing, seriousness, and relatedness of AEs, and laboratory abnormalities will be 
recorded and reported. 
Patients stopping randomized treatment early because of unacceptable AEs will be followed 
until resolution or stabilization of the AEs in question.  
Pharmacokinetic Assessments: 
Blood samples will be collected only for the balixafortide+ eribulin treatment arm to: 
• 
Evaluate the PK of balixafortide and its metabolite levels in patients on the balixafortide 
+ eribulin treatment arm. 
• 
Support the data from the immunogenicity assessment by evaluating the PK of 
balixafortide. 
The plasma concentration of balixafortide will be integrated into the population PK model 
generated using PK data from previous clinical studies. 
Additional PK samples, taken up to 48 hours after the last dose in approximately 15 patients, 
will allow monitoring of drug clearance after dosing has ceased. 
General Statistical Considerations: 
The data from this study will serve a dual purpose:  
(i) To provide efficacy and safety data in the Overall Population for regulatory 
submissions in the EU and jurisdictions in which the 2nd line + eribulin label applies. 
(ii) To provide efficacy and safety data in the 3rd line + population for regulatory 
submissions in the US and jurisdictions in which the 3rd line + eribulin label applies.  
For the Overall Population, the critical efficacy endpoints shall be PFS and OS. For the 
3rd line + population, the critical efficacy endpoints shall be ORR, PFS and OS.  
In the Overall Population, the formal analysis of PFS is event driven and is expected to be 
conducted when all patients have been followed for a minimum of 12 months. An interim 
analysis of OS will be performed at the same time as the analysis of PFS and a final analysis 
of OS will take place once all patients have been followed for a minimum of 24 months. 
In the 3rd line + population, the analysis of objective response is planned once all such 
patients have been randomized and followed for a minimum of 6 months. The formal analysis 
of PFS is event driven and planned when all 3rd line + patients have been followed for a 
minimum of 12 months. An interim analysis of OS will be performed at the same time as the 
analysis of PFS, and a final analysis of OS will take place once all 3rd line + patients have 
been followed for a minimum of 24 months. 
 
Alpha allocation and recycling will ensure control of the overall Type I error rate for (i) the 
Overall Population and (ii) 3rd line + population separately.  
 
Overall Population Efficacy Plan relevant to the EU and other jurisdictions in which the 
2nd line + Eribulin Label applies: 
Sample Size 
Assuming a median PFS on eribulin of 3.9 months, to test for a hazard ratio versus balixafortide 
+ eribulin of 0.699 (corresponding to a median PFS of 5.6 months), a total of 346 PFS events 
are required to provide 90% power at the 1-sided 2.0% alpha level. Equally, 346 PFS events 
provides 94.6% power for a hazard ratio of 0.674, corresponding to a PFS of 5.8 months. 
Assuming a 12-month, non-linear recruitment period (η=2; Carroll, 2009) and a minimum 12-
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month follow-up period after the last patient is randomized, a total of 384 patients will be 
recruited. 
 
Statistical Methods 
Patient demographics and clinical characteristics will be summarized using descriptive 
statistics. 
 
Efficacy Analysis 
Primary Endpoint: PFS time (defined as the time from randomization to the first progression or 
death, as judged by an IRC) is the primary endpoint in the Overall Population.  PFS will be 
analyzed via Cox regression modelling in the intent-to-treat (ITT) population. Patients free from 
progression and death will be censored at their last follow-up visit. The analysis will be stratified 
for randomization stratification factors and a fixed effect term will be included for randomized 
treatment. The hazard ratio will be estimated from the model along with the associated 
confidence interval (CI) and 2-sided p value. The data will also be displayed using Kaplan-
Meier curves and median PFS times will be estimated. 
 
Key Secondary Endpoints: OS will be the key secondary efficacy endpoint in the Overall 
Population. OS will be analyzed in a fashion similar to that described for PFS.  
 
The statistical design in the 2nd line + population, with pre-defined alpha allocation and 
recycling, is such that if PFS does not meet statistical significance at its allocated alpha level, 
then the design still allows OS to be tested and, if it meets statistical significance at its allocated 
alpha level, then the study can still be formally positive for efficacy.  
  
Type I error Control for Primary and Key Secondary Efficacy Endpoints: The formal analysis of 
PFS will take place once 346 PFS events have accrued and is expected when all randomized 
patients have been followed for a minimum of 12 months. The alpha allocation for this analysis 
will be 0.040 2-sided. At the time of the planned PFS analysis, an interim analysis of OS will be 
performed with an alpha allocation of 0.002 2-sided. A final analysis of OS will take place once 
all randomized patients have been followed for a minimum of 24 months. The alpha allocation 
for this analysis will be between 0.008 and 0.05 2-sided depending on the results of previous 
analyses. Thus, for the Overall Population, there will be a total of 3 formal efficacy analyses 
(PFS, interim OS and final OS). The overall Type I error rate will be controlled at 0.05 by means 
of alpha allocation and recycling. 
 
Other Secondary Endpoints:  
Analysis of the other secondary endpoints of objective response rate (ORR), clinical benefit 
rate (CBR), disease control rate (DCR), time to response, and duration of response will not be 
subject to Type I error control. Statistical tests will be 2-sided with a nominal Type I error rate 
of 0.05.  
Exploratory Endpoints: The European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30), EuroQoL-5D (EQ-5D) and 
Functional Assessment of Cancer Therapy Breast (FACT-B) will be compared between 
randomized treatments over time. The relationship between baseline biomarkers (including ER 
status, PgR status, CXCR4 expression levels, cytokines [eg IFN-gamma], immune cells profile 
and ribonucleic acid [RNA] expression) and ORR, PFS and OS will be explored using a variety 
of exploratory data analysis.  
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3rd line + Population Efficacy Plan relevant to the US and other jurisdictions in which the 
3rd line + Eribulin Label applies: 
Sample Size 
Assuming a median PFS on eribulin of 3.9 months, to test for a hazard ratio versus balixafortide 
+ eribulin of 0.674 (corresponding to a median PFS of 5.8 months), a total of 286 PFS events 
are required to provide 90% power at the 1-sided 2.0% alpha level. Assuming a 12-month, non-
linear recruitment period (η=2; Carroll, 2009(3)) and a minimum 12-month follow-up period after 
the last patient is randomized, a total of 320 3rd line + patients will be recruited.  
 
Statistical Methods 
Patient demographics and clinical characteristics will be summarized using descriptive 
statistics. 
 
Efficacy Analysis 
Co-Primary Endpoints: In the 3rd line+ population ORR (CR + PR) and PFS are co-primary 
endpoints population.  
ORR (CR + PR) will be analyzed by exact logistic regression and will be stratified for 
randomization stratification factors. The odds ratio will be estimated from the model along with 
the associated CI and 2-sided p-value.  
PFS will be analyzed using the same methodology as described for the 2nd line + population. 
Key Secondary Endpoints:  OS is the key secondary efficacy endpoint. OS will be analyzed 
using the same methodology as described for the 2nd line + population.  
The statistical design in the 3rd line + population, with pre-defined alpha allocation and recycling, 
is such that even if ORR does not meet statistical significance at its allocated alpha level, then 
PFS can still be tested and, if it meets statistical significance at its allocated alpha level, the 
study can still meet its primary objective. Further, if PFS does not meet statistical significance 
at its allocated alpha level, then OS can still be tested and, if it meets statistical significance at 
its allocated alpha level, then the study can still be formally positive for efficacy.  
Type I error Control for Co-Primary and Key Secondary Efficacy Endpoints: The formal analysis 
of ORR is planned for the 3rd line + population once all such patients have been randomized 
and followed for a minimum of 6 months. The alpha allocation for this analysis will be 0.001 2-
sided. The formal analysis of PFS will take place once 286 PFS events have accrued, being 
expected when all randomized patients have been followed for a minimum of 12 months (this 
analysis is anticipated to coincide with the planned analysis of PFS in the 2nd line + population). 
The alpha allocation for this analysis will be 0.040 2-sided; if the PFS in the 3rd line + population 
meets the allocated alpha level, PFS in the Overall Population will also be formally tested at 
the same alpha level; further, at the time of the PFS analysis an interim analysis of OS will be 
performed with an alpha allocation of 0.001 to 0.002 2-sided, depending on the result of the 
previous ORR analysis. The final analysis of OS will take place once all randomized patients 
have been followed for a minimum of 24 months at which time 226 events are expected (again, 
this analysis is anticipated to coincide with the planned analysis of OS in the 2nd line + 
population). The alpha allocation for this analysis will be between 0.008 and 0.05 2-sided 
depending on the results of previous analyses. Thus, there will be a total of 5 formal efficacy 
analyses in the 3rd line + population (ORR, PFS, PFS in the Overall Population if PFS is met in 
the 3rd line+ population, interim OS and final OS). The overall Type I error rate will be controlled 
at 0.05 by means of alpha allocation and recycling. 
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Other Secondary Endpoints: Analysis of the other secondary endpoints of CBR, DCR, 
time to response, and duration of response will be conducted in the same manner as 
described for the 2nd line + population. 
Exploratory Endpoints: EORTC-QLQ-C30, EQ-5D, FACT-B the relationship between baseline 
biomarkers and efficacy outcomes will be analyzed in the same manner as described for the 
2nd line + population.  
Safety Analysis 
The Safety Population is defined as all randomized patients who received at least 1 dose (or 
partial dose) of study medication regardless of line of therapy. Summaries of AEs and other 
safety parameters will be provided by treatment arm received, based on the first dose of study 
drug. 
AEs will be classified using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. The severity will be graded according to the NCI CTCAE v5.0 
whenever possible. All AEs reported from the first dose of study drug until 30 days after the last 
dose of study drug will be considered as treatment-emergent AEs (TEAEs) and will be 
summarized descriptively by treatment, and by the frequency of patients experiencing TEAEs 
corresponding to body systems and MedDRA preferred term. Patients with multiple 
occurrences of events will only be counted once at the maximum severity/grade to study drug 
for each Preferred Term, System Organ Class (SOC), and overall. Any AEs with missing 
severity or relationship to study drug will be classified as severe and treatment-related, 
respectively. Deaths that occur within 30 days after the last dose of study drug are defined as 
on-study deaths. 
All AEs will be summarized by relatedness to study medication and may be summarized by 
cycle as warranted. Detailed information collected for each AE will include a description of the 
event, duration, whether the AE was serious, severity, relationship to study drug, action taken, 
and clinical outcome.  
Any AEs leading to death or discontinuation of study medication, events classified as NCI 
CTCAE v5.0 Grade 3 or higher, AESIs (Section 9.2.6), study drug-related events, and SAEs 
will be monitored with special attention. 
The format and content of summary tables and individual patient listings is described in the 
Statistical Analysis Plan (SAP).  
Scheduled physical examination, vital signs, and hematology and chemistry laboratory data will 
be summarized by treatment and by cycle. The laboratory results will be graded according to 
the NCI CTCAE v5.0 severity grade. The frequencies of the worst severity grade observed will 
be displayed by study medication. Shift tables will be provided to examine the distribution of 
laboratory toxicities. For parameters for which an NCI CTCAE v5.0 scale does not exist, the 
frequency of patients with values below, within, and above the normal ranges will be 
summarized by treatment. 
Data Safety Monitoring Committee: An independent Data Safety Monitoring Committee 
(DSMC) will be established with the responsibility of safeguarding the safety of study 
participants. The DSMC will review accumulating safety data during the conduct of this 
open label study and the interim analyses. The DSMC will provide ongoing review and 
recommendations to the Sponsor as necessary in relation to study conduct and patient 
management. The composition and operation of the DSMC is described in the DSMC 
charter. 
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1.1 
Study Schedule 
1.1.1 
Schedule of Assessments for Balixafortide + Eribulin Treatment Arm 
1.1.1.1 Screening, Cycle 1, and Cycle 2 
Table 1 
Schedule of Assessments for Balixafortide + Eribulin Treatment Arm: Screening, Cycle 1, and Cycle 2 
Visits (Visit  
Window days) 
Section number 
 
Screening  
(-21 to -1) 
Active treatment phase (21 Days per cycle) 
Cycle 1 
Cycle 2 
D1 
D2 
D3 
D8 
D9 
D10 
D1 
D2 
D3 
D8 
D9 
D10 
D21 
Assessment  
Informed consent 
15.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IWRS/IRT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion/exclusion criteria 
5.1 & 5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics (gender, date of birth, race, 
ethnicity) and baseline data 
− 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient reported health outcomes 
11.3 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Physical examination[1] 
9.6 
X[2] 
X[3] 
 
 
 
 
 
X[3] 
 
 
 
 
 
 
Vital signs (body temperature, resting blood 
pressure, respiratory rate, pulse rate)[1] 
9.7 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Weight, height[4] 
9.6 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
ECOG performance status 
9.6 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Adverse events 
9.1 & 9.2 
X[5] 
X-----------------------------------------------------------------------------------------------------------------------------------X 
Prior/Concomitant medications 
5.4.1 
X 
X-----------------------------------------------------------------------------------------------------------------------------------X 
Clinical Laboratory tests[1]  
9.9 
X[6] 
X[7] 
 
 
X[7] 
 
 
X[7] 
 
 
X[7] 
 
 
 
Pregnancy test 
5.4.5.1 
X[8] 
X[9] 
 
 
 
 
 
X[9] 
 
 
 
 
 
 
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Visits (Visit  
Window days) 
Section number 
 
Screening  
(-21 to -1) 
Active treatment phase (21 Days per cycle) 
Cycle 1 
Cycle 2 
D1 
D2 
D3 
D8 
D9 
D10 
D1 
D2 
D3 
D8 
D9 
D10 
D21 
Assessment  
Contraceptive advice 
5.4.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI scan[10, 11] 
8.2 
X[12] 
 
 
 
 
 
 
 
 
 
 
 
 
X[10] 
Bone scan 
8.2 
X[12, 13] 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG[1] 
9.8 
X 
X 
X 
 
 
X 
 
 
X[14] 
 
 
X[14] 
 
 
Document date and results of last tumor 
biopsy/fresh tumor biopsy 
11.2.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for PK 
10.1 
 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
 
 
Blood for immunogenicity testing 
11.1 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Blood for exploratory biomarkers in all 
patients[15] 
11.2.2 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Confirmation of eligibility and randomization 
5.1 & 5.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Balixafortide treatment[16] 
6.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Eribulin treatment 
6.1 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For patients at selected sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional tumor biopsy[17] 
11.2.1 
X 
 
 
 
 
 
 
 
 
 
 
X[18] 
 
 
Blood for other exploratory biomarkers 
11.2.2 
 
X 
X 
 
X 
 
 
 
 
 
 
X[19] 
 
 
MRI: magnetic resonance imaging; RECIST: Response Evaluation Criteria In Solid Tumors; SAE: serious adverse event. Footnotes: 
1. 
Additional assessments to those scheduled for this study should be performed as indicated at the Investigator's discretion (e.g. due to concerns about patient safety, 
patient's clinical status); the findings of an unscheduled examination should be recorded in the patient's source data and eCRF.  
2. 
Standard, complete physical examination. 
3. 
Targeted physical examination.  
4. 
Height will be measured at Screening only.  
5. 
SAEs will be recorded from the date that the informed consent form is signed. 
6. 
Screening blood tests should be taken within 7 days prior to randomization. 
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7. 
Blood test results must be available within 24 hours prior to study medication administration.  
8. 
Serum pregnancy test for women of child bearing potential only, no more than 7 days prior to Randomization. More frequent assessments can be performed if 
medically indicated as determined by the Investigator, and these evaluations will be recorded in the patient’s source data and eCRF.   
9. 
Urine pregnancy test for women of child bearing potential only.  
10. CT/MRI scan will be performed at Screening, then from the date of randomization every 6 weeks (±7 days) during the first year, and then every 12 weeks (±7 days), 
thereafter, until PD is documented by RECIST v1.1. It is critical that tumor assessments are performed according to the Study Schedule in a timely and complete 
manner regardless of any dosing delay or interruption. Imaging assessments will be scheduled using the randomization date as the reference date for all timepoints 
and NOT scheduled according to the date of the previous timepoint. A delay in the imaging assessment to accommodate a treatment delay is not permitted. Following 
initial documentation of an objective response, a confirmatory CT/MRI scan will be performed at least 4 weeks later. 
11. At the discretion of the Investigator, additional radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression; the 
results of the unscheduled scan should be recorded in the patient's source data and eCRF.  
12. Record date and results of last scan on the patient's source data and eCRF. If no scan has been performed in the 30 days prior to Randomization a scan should be 
performed during Screening.  
13. From the date of randomization, additional bone scans will be performed at the discretion of the Investigator.  
14. After Cycle 2, the frequency of ECGs can be reduced to every 2 cycles if deemed clinically appropriate (i.e. absence of ECG findings in earlier assessments).  
15. Blood will be collected from all patients to assess plasma levels of interferon gamma and additional cytokine markers. 
16. Patients will start study medication within 3 days from randomization. 
17. Patients at selected sites can optionally consent to fresh tumor biopsy at Screening and subsequent timepoints. If a biopsy has already been performed within 30 days 
prior to Randomization and tumor tissue is still available, then the fresh tumor biopsy is not required during Screening. 
18. Alternatively, can be performed on Day 10 if preferred. 
19. A blood sample will be taken only in patients at selected sites who are scheduled to have an optional, fresh tumor biopsy; the blood sample can be taken before or 
after the biopsy. 
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1.1.1.2 Cycle 3, Subsequent Cycles, and Post-treatment Phase  
Table 2 
Schedule of Assessments for Balixafortide + Eribulin Treatment Arm: Cycle 3, Subsequent Cycles, and Post-
treatment Phase 
Visits (Visit  
Window days) 
Section number 
 
Active treatment phase (21 Days per cycle) 
Post-treatment phase  
Cycle 3 
Subsequent Cycles 
EoT 
(+7)  
30-day 
safety 
FU (+7) 
Long-
term 
FU 
(±7)[1] 
 
D1 
D2 
D3 
D4 
D5 
D8 
D9 
D10 
D1 
D2 
D3 
D8 
D9 
D10 
D21 
 
 
 
Assessment  
IWRS/IRT 
- 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Patient reported health 
outcomes 
11.3 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Targeted physical 
examination[2] 
9.6 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Vital signs (body 
temperature, resting blood 
pressure, respiratory rate, 
pulse rate)[2] 
9.7 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Weight 
9.6 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
ECOG performance 
status 
9.6 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Adverse events 
9.1 & 9.2
X------------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
Prior/Concomitant 
medications 
5.4.1 
X-----------------------------------------------------------------------------------------------------------------------------------------------------X 
X[3] 
 
Clinical Laboratory tests[2]  
9.9 
X[4] 
 
 
 
 
X[4] 
 
 
X[4] 
 
 
X[4] 
 
 
 
X 
 
 
Pregnancy test 
5.4.5.1 
X[5] 
 
 
 
 
 
 
 
X[5] 
 
 
 
 
 
 
X[5] 
 
 
CT/MRI scan[6, 7] 
8.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X[6] 
X[8] 
 
X[1] 
Bone scan[9] 
8.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Visits (Visit  
Window days) 
Section number 
 
Active treatment phase (21 Days per cycle) 
Post-treatment phase  
Cycle 3 
Subsequent Cycles 
EoT 
(+7)  
30-day 
safety 
FU (+7) 
Long-
term 
FU 
(±7)[1] 
 
D1 
D2 
D3 
D4 
D5 
D8 
D9 
D10 
D1 
D2 
D3 
D8 
D9 
D10 
D21 
 
 
 
Assessment  
12-lead ECG[2] 
9.8 
 
X[10] 
 
 
 
 
X[10] 
 
 
X[10] 
 
 
X[10] 
 
 
X 
 
 
Blood for PK 
10.1 
 
X 
 
X[11] 
X[11] 
 
 
 
 
X[12] 
X[12] 
 
 
 
 
 
 
 
Blood for immunogenicity 
testing 
11.1 
X 
 
 
 
 
 
 
 
X[13] 
 
 
 
 
 
 
X 
 
 
Blood for exploratory 
biomarkers in all 
patients[14] 
11.2.2 
X 
X 
X 
X[15] 
X[15] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Balixafortide treatment 
6.1 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Eribulin treatment 
6.1 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Document reason for 
treatment discontinuation 
− 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Survival status, PD 
monitoring, all anticancer 
medicines received 
7.8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For patients at selected 
sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional tumor biopsy 
11.2.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Blood for other 
exploratory biomarkers 
11.2.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
AE: adverse event; MRI: magnetic resonance imaging; RECIST: Response Evaluation Criteria In Solid Tumors. Footnotes: 
1. 
Regardless of treatment arm, patients discontinued from study medication for any reason, in the absence of PD, will undergo repeat imaging and tumor response 
assessments (including CT/MRI scans) every 8 weeks ±7 days (every 12 weeks ±7 days if the patient has been on the study for ≥1 year) until PD is documented as 
per RECIST v1.1, or death occurs, or the patient is lost to follow-up, or the patient withdraws consent (whichever occurs first). Once PD is recorded, the patient will be 
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followed every 6 months (or more frequently) for Survival Follow-up only, until the patient dies, withdraws consent, or is lost to follow-up (whichever occurs first). 
Survival follow-up can be conducted by telephone. 
2. 
Additional assessments to those scheduled for this study should be performed as indicated at the Investigator's discretion (e.g. due to concerns about patient safety, 
patient's clinical status); the findings of an unscheduled examination should be recorded in the patient's source data and eCRF.  
3. 
Concomitant therapy/medications taken since previous visit to be recorded for patients with unresolved AEs. 
4. 
Blood test results must be available within 24 hours prior to study medication administration.  
5. 
Urine pregnancy test for women of child bearing potential only.  
6. 
CT/MRI scan will be performed at Screening, then from the date of randomization every 6 weeks (±7 days) during the first year, and then every 12 weeks (±7 days), 
thereafter, until PD is documented by RECIST v1.1. It is critical that tumor assessments are performed according to the Study Schedule in a timely and complete 
manner regardless of any dosing delay or interruption. Imaging assessments will be scheduled using the randomization date as the reference date for all timepoints 
and NOT scheduled according to the date of the previous timepoint. A delay in the imaging assessment to accommodate a treatment delay is not permitted. Following 
initial documentation of an objective response, a confirmatory CT/MRI scan will be performed at least 4 weeks later. 
7. 
At the discretion of the Investigator, additional radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression; the 
results of the unscheduled scan should be recorded in the patient's source data and eCRF.  
8. 
CT/MRI scans will be performed in patients who are discontinued from study medication in the absence of PD; however, patients who have already demonstrated 
objective PD (according to RECIST v 1.1) do not need to have scans repeated at the EoT visit.  
9. 
From the date of randomization, additional bone scans will be performed at the discretion of the Investigator.  
10. After Cycle 2, the frequency of ECGs can be reduced to every 2 cycles if deemed clinically appropriate (i.e. absence of ECG findings in earlier assessments).  
11. For patients at selected sites only. 
12. Cycle 5 and Cycle 7 only. 
13. After Cycle 3, blood samples are taken on Day 1 of every alternate cycle (e.g. Cycle 5, Cycle 7, Cycle 9 etc). 
14. Blood will be collected from all patients to assess plasma levels of interferon gamma and additional cytokine markers. 
15. Only in patients at selected sites scheduled to have PK sampling. 
 
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1.1.2 
Schedule of Assessments for Eribulin Monotherapy Treatment Arm 
Table 3 
Schedule of Assessments for Eribulin Monotherapy Treatment Arm 
 
Section number 
 
Screening  
(-21 to -1) 
Active treatment phase (21 Days per cycle) 
Post-treatment phase 
 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent Cycles 
EOT  
(+7) 
30-day 
safety FU 
(+7) 
Long-term 
FU (±7)[1] 
 
D2 
D9 
D2 
D9 
D21 
D2 
D9 
D2 
D9 
D21 
Assessment  
Informed consent 
15.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IWRS/IRT 
- 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
Inclusion/exclusion criteria 
5.1 & 5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics (gender, date of 
birth, race, ethnicity) and baseline 
data 
− 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient reported health outcomes 
11.3 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
Physical examination[2] 
9.6 
X[3] 
X[4] 
 
X[4] 
 
 
X[4] 
 
X[4] 
 
 
X[4] 
 
 
Vital signs (body temperature, 
resting blood pressure, respiratory 
rate, pulse rate)[2] 
9.7 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
Weight, height[5] 
9.6 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
ECOG performance status 
9.6 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
Adverse events 
9.1 & 9.2 
X[6] 
X--------------------------------------------------------------------------------------------------------------------------------X 
 
Prior/Concomitant medications 
5.4.1 
X 
X-----------------------------------------------------------------------------------------------------------------X 
X[7] 
 
Clinical laboratory tests[2] 
9.9 
X[8] 
X[9] 
X[9] 
X[9] 
X[9] 
 
X[9] 
X[9] 
X[9] 
X[9] 
 
X 
 
 
Pregnancy test 
5.4.5.1 
X[10] 
X[11] 
 
X[11] 
 
 
X[11] 
 
X[11] 
 
 
X[11] 
 
 
Contraceptive advice 
5.4.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section number 
 
Screening  
(-21 to -1) 
Active treatment phase (21 Days per cycle) 
Post-treatment phase 
 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent Cycles 
EOT  
(+7) 
30-day 
safety FU 
(+7) 
Long-term 
FU (±7)[1] 
 
D2 
D9 
D2 
D9 
D21 
D2 
D9 
D2 
D9 
D21 
Assessment  
CT/MRI scan[12,13] 
8.2 
X[14] 
 
 
 
 
X[12] 
 
 
 
 
X[12] 
X[15] 
 
X[1] 
Bone scan 
8.2 
X[14, 16] 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG[2] 
9.8 
X 
X 
X 
X [17] 
X[17] 
 
X[17] 
X[17] 
X[17] 
X[17] 
 
X 
 
 
Document date and results of last 
tumor biopsy/fresh tumor biopsy 
11.2.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for exploratory biomarkers in 
all patients[18] 
11.2.2 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
 
Confirmation of eligibility and 
randomization 
5.1 & 5.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eribulin treatment[19] 
6.1 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Document reason for treatment 
discontinuation 
− 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Survival status, PD monitoring, all 
anticancer medicines received 
7.8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For patients at selected sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional tumor biopsy[20] 
11.2.1 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Blood for other exploratory 
biomarkers  
11.2.2 
 
X 
 
 
X[21] 
 
X 
 
 
 
 
X 
 
 
AE: adverse event; RI: magnetic resonance imaging; RECIST: Response Evaluation Criteria In Solid Tumors; SAE: serious adverse event. Footnotes: 
1. 
Regardless of treatment arm, patients discontinued from study medication for any reason, in the absence of PD, will undergo repeat imaging and tumor response 
assessments (including CT/MRI scans) every 8 weeks ±7 days (every 12 weeks ±7 days if the patient has been on the study for ≥1 year) until PD is documented as 
per RECIST v1.1, or death occurs, or the patient is lost to follow-up, or the patient withdraws consent (whichever occurs first). Once PD is recorded, the patient will be 
followed every 6 months (or more frequently) for Survival Follow-up only, until the patient dies, withdraws consent, or is lost to follow-up (whichever occurs first). 
Survival follow-up can be conducted by telephone. 
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2. 
Additional assessments to those scheduled for this study should be performed as indicated at the Investigator's discretion (e.g. due to concerns about patient safety, 
patient's clinical status); the findings of an unscheduled examination should be recorded in the patient's source data and eCRF.  
3. 
Standard, complete physical examination. 
4. 
Targeted physical examination.  
5. 
Height will be measured at Screening only.  
6. 
SAEs will be recorded from the date that the informed consent form is signed. 
7. 
Concomitant therapy/medications taken since previous visit to be recorded for patients with unresolved AEs. 
8. 
Screening blood tests should be taken within 7 days prior to randomization. 
9. 
Blood test results must be available within 24 hours prior to study medication administration.  
10. Serum pregnancy test for women of child bearing potential only, no more than 7 days prior to Randomization. More frequent assessments can be performed if 
medically indicated as determined by the Investigator, and these evaluations will be recorded in the patient’s source data and eCRF.    
11. Urine pregnancy test for women of child bearing potential only.  
12. CT/MRI scan will be performed at Screening, then from the date of randomization every 6 weeks (±7 days) during the first year, and then every 12 weeks (±7 days), 
thereafter, until PD is documented by RECIST v1.1. It is critical that tumor assessments are performed according to the Study Schedule in a timely and complete 
manner regardless of any dosing delay or interruption. Imaging assessments will be scheduled using the randomization date as the reference date for all timepoints 
and NOT scheduled according to the date of the previous timepoint. A delay in the imaging assessment to accommodate a treatment delay is not permitted. Following 
initial documentation of an objective response, a confirmatory CT/MRI scan will be performed at least 4 weeks later. 
13. At the discretion of the Investigator, additional radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression; the 
results of the unscheduled scan should be recorded in the patient's source data and eCRF.  
14. Record date and results of last scan on the patient's source data and eCRF. If no scan has been performed in the 30 days prior to Randomization a scan should be 
performed during Screening. 
15. CT/MRI scans will be performed in patients who are discontinued from study medication in the absence of PD; however, patients who have already demonstrated 
objective PD (according to RECIST v 1.1) do not need to have scans repeated at the EoT visit.  
16. From the date of randomization, additional bone scans will be performed at the discretion of the Investigator.  
17. After Cycle 2, the frequency of ECGs can be reduced to every 2 cycles if deemed clinically appropriate (i.e. absence of ECG findings in earlier assessments).  
18. Blood will be collected from all patients to assess plasma levels of interferon gamma and additional cytokine markers. 
19. Patients will start study medication within 3 days from randomization. 
20. Patients at selected sites can optionally consent to fresh tumor biopsy at Screening and subsequent timepoints. If a biopsy has already been performed within 30 days 
prior to Randomization and tumor tissue is still available, then the fresh tumor biopsy is not required during Screening. 
21. A blood sample will be taken only in patients at selected sites who are scheduled to have an optional, fresh tumor biopsy; the blood sample can be taken before or 
after the biopsy. 
 
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2. 
INTRODUCTION 
2.1 
Background on the Disease to be Treated 
Breast cancer (BC) is the most common cancer in women worldwide with nearly 1.7 million 
new cases diagnosed in 2012, representing 25% of all cancers in women (4). In Europe, there 
were an estimated 464000 new cases of BC (female) in 2012 and an estimated 131000 deaths 
from the disease (5). Deaths from BC among women accounted for 16.2% of all deaths from 
cancer (6) and metastatic BC has a 5-year relative survival rate of about 22% (7). 
Hormonal therapy is the initial course of treatment for those BCs that are estrogenic-receptor 
positive (ER+) whereas chemotherapy is the initial treatment course for patients who are 
estrogenic-receptor negative (ER-). Unfortunately, hormone therapy often leads to drug 
resistance requiring ER+ patients to also rely on chemotherapy to control their disease. 
However, there is no single preferred first-line chemotherapy; after failure of initial 
chemotherapy, treatment options are few and cumulative toxicity from previous therapy can 
also be a problem. Therefore, there remains a need for more and better therapeutics to treat 
metastatic BC that improve clinical outcomes (including the response rate and time to 
progression) and safety profile (8, 9).  
C-X-C chemokine receptor type 4 (CXCR4) is principally expressed by hematopoietic stem 
cells and immune cells, and its main physiological role is to regulate their function and 
trafficking. It is also overexpressed in over 20 human tumor types (including primary and 
metastatic BC). Its natural ligand, stromal cell-derived factor-1 (SDF-1), is highly expressed at 
prevalent sites of BC metastases: lymph nodes, bone marrow, bone, lung and liver (10-13). 
The CXCR4/SDF-1 axis promotes cancer growth by allowing tumor immune evasion and 
creating a pro-tumor microenvironment within the metastatic niche; it may also protect BC 
cells from cytotoxic therapy (14-19). CXCR4 expression correlates with aggressive metastatic 
phenotypes and poor prognosis in BC (14, 20, 21). The increased risk appears to be 
independent of any particular BC subtype, stage, or type of adjuvant therapy (20).  
After failure of initial chemotherapy, there is no clinical standard of care for human epidermal 
growth factor receptor 2 (HER2) negative patients with metastatic BC. Eribulin is indicated for 
the treatment of adult patients with locally advanced or metastatic BC who have progressed 
after at least one chemotherapeutic regimen for advanced disease (prior therapy should have 
included an anthracycline and a taxane in either the adjuvant or metastatic setting unless 
patients were not suitable for these treatments). The eribulin approvals were based on the 
Phase 3, EMBRACE study in women with locally recurrent or metastatic BC. Most women in 
this study were HER2 negative and all received 3rd line therapy, or beyond, with either eribulin 
or treatment of physician's choice. The EMBRACE study provided a median overall survival 
(OS) of 13.1 versus 10.6 months respectively (22).  
In another Phase 3 study of patients with locally advanced or metastatic BC, previously treated 
with an anthracycline or taxane, and most of whom were HER2 negative, eribulin showed a 
similar median OS to capecitabine (15.9 versus 14.5 months) (23). A pooled analysis of 
patients with metastatic BC (who met the criteria in the European Union [EU] Summary of 
Product Characteristics [SmPC] to receive eribulin, and most of whom were HER2 negative) 
suggested that eribulin was associated with a longer median OS than capecitabine (15.1 
versus 12.0 months) (24).  
Despite the advent of new therapies, metastatic BC remains an essentially incurable disease. 
There is a huge need for treatments that improve OS for women with recurrent or advanced 
metastatic BC, particularly those patients who have received multiple prior therapies. Many 
patients either do not respond to available treatments or develop resistance to approved 
agents such as anthracyclines and taxanes. 
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2.2 
Balixafortide 
Balixafortide (POL6326) is a potent, selective antagonist of the highly conserved human 
CXCR4 receptor as demonstrated by in vitro receptor binding studies. Balixafortide is a cyclic 
synthetic peptide consisting of 16 amino acids with a disulfide bridge between the two 
Cysteines: Cys4 and Cys11. All amino acid residues except for D-Pro7 and D-Pro15 are in 
the L-configuration. Acetic acid is present in a non-stoichiometric ratio.   
Product code name: 
POL6326 
INN 
Balixafortide 
Chemical Name:  
Cyclo(-L-tyrosyl-L-histidyl-L-alanyl-L-cysteinyl-L-seryl-L-alanyl-D-
prolyl-L-2,4-diaminobutyryl-L-arginyl-L-tyrosyl-L-cysteinyl-L-
tyrosyl-L-glutaminyl-L-lysyl-D-prolyl-L-prolyl) (4 →11) disulfide, 
acetate salt 
Chemical Name 
(Abbreviated): 
Cyclo(-Tyr-His-Ala-Cys-Ser-Ala-D-Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-
Lys-D-Pro-Pro), disulfide bond between Cys4 and Cys11, acetate 
salt or 
Cyclo(-Tyr-His-Ala-Cys-Ser-Ala-D-Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-
Lys-D-Pro-Pro) Cys4 → Cys11 disulfide, acetate salt 
Molecular Weight: 
1864.1 g/mol (net) 
Molecular Formula: 
C84H118N24O21S2 (net) 
 
As summarized by Teicher et al, 2010 (25), interference with the CXCR4/SDF-1 axis may 
directly suppress tumor growth through disruption of survival signaling pathways driven by 
CXCR4 (Figure 1). 
Figure 1 Downstream signaling pathways linked with SDF-1/CXCR4 signaling  
 
Source: Teicher et al 2010 (25) 
 
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Preclinical evidence suggests that disrupting this pathway may prevent the development of 
distant BC metastases (26-29). 
Furthermore, it has been shown that high levels of CXCR4 expression in primary tumors and 
metastases are associated with aggressive metastatic phenotypes, a negative prognosis, and 
poor survival in BC (14, 20, 21, 30).  
Recent strategies have focused on the potential of CXCR4 antagonists to enhance the 
cytotoxic effect of chemotherapy, both directly and via regulation of the tumor 
microenvironment to enhance endogenous anti-tumor responses (15, 17, 28, 31). In addition,  
recent evidence in both preclinical models (32) and in the clinical setting (33), suggests that 
antagonism of CXCR4 might counteract tumor cells immune-evasion by altering immune cell 
distribution and/or activity in the tumor microenvironment. 
Besides published data on the potential modes of action of CXCR4 antagonists, preclinical 
data indicate that POL5551 (an analogue of balixafortide) and eribulin showed an enhanced 
cytotoxic effect, as well as inhibition of metastases, in triple-negative BC models (34). In 
addition, in preclinical models POL5551 has been demonstrated to enhance sensitivity to 
chemotherapy in pediatric acute lymphoblastic leukemia (35), target glioblastoma stem cells 
(36), and disrupt anti-vascular endothelial growth factor therapy-induced glioma dissemination 
(37). 
The clinical effect in the form of cluster of differentiation 34+ (CD34+) stem cell and white 
blood cell (WBC) release, as demonstrated with balixafortide and described above in 
completed and ongoing Phase 1 trials (38), confirms that balixafortide effectively interacts and 
blocks the CXCR4 receptor in these clinical settings. This clinical activity might be considered 
a surrogate marker for use in oncology indications, where the focus is less on actual release 
of cells but rather on general interference with the SDF-1/CXCR4 signaling. Disrupting this 
interaction, by administering balixafortide to patients with metastatic BC, is expected to 
enhance the cytotoxic effect of chemotherapy both directly and via regulation of the tumor 
microenvironment to enhance endogenous anti-tumor responses.  
In an ongoing Phase 1 clinical trial sponsored by Polyphor (study POL6326-007), the 
combination of balixafortide and eribulin is being studied in HER2 negative metastatic BC 
patients with evidence of CXCR4 tumor cell expression in historical tissue samples. At the 
interim analysis in patients who received 2nd to 5th line treatment, safety, tolerability and activity 
data were encouraging. The Phase 1 data indicate that the objective response rate (ORR) and 
clinical benefit rate (CBR) achieved with the combination of balixafortide and eribulin are 
considerably higher numerically than those reported for eribulin monotherapy in the literature. 
These observations are most pronounced for the Expanded Cohort of patients receiving 
eribulin + 5.5 mg/kg balixafortide where ORR was 38%, CBR was 63%, the median 
progression free survival (PFS) was 6.2 months, and 12-month OS was 75%. In contrast, the 
figures reported for eribulin monotherapy in the literature are ORR 9-12%, CBR 17%, median 
PFS of 2.6−4.1 months and 12-month OS of 54%) (22, 23, 39-41). In the Phase 1 trial, the 
safety and tolerability of balixafortide + eribulin appear comparable to published data on either 
eribulin or balixafortide monotherapy (41). 
Thus, Polyphor is developing balixafortide as an intravenous (IV) therapy for metastatic BC, 
in combination with eribulin. Balixafortide’s novel mechanism of action and its combination 
with an established approved therapy is intended to improve disease control (reduce tumor 
burden and/or provide a period of disease stabilization) in patients with HER2 negative 
metastatic BC. 
The dosing schedule used in the Expanded Cohort of the Phase 1 trial is the same as the 
dosing schedule that is proposed for this pivotal trial. This regimen allows for maximum 
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disruption of the protective tumor microenvironment (e.g. blockade of pro-survival SDF-1 
signaling, change in distribution and activation of immunosuppressive cells) by balixafortide in 
combination with eribulin. 
2.3 
Eribulin 
Eribulin mesylate is a microtubule dynamics inhibitor belonging to the halichondrin class of 
antineoplastic agents. It is a structurally simplified synthetic analogue of halichondrin B, a 
natural product isolated from the marine sponge Halichondria okadai. 
Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and 
sequesters tubulin into non-productive aggregates. Eribulin exerts its effects via a tubulin-
based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, 
and, ultimately, apoptotic cell death after prolonged and irreversible mitotic blockage (42). 
Eribulin was first approved in the United States (US) in 2010 and in the EU in 2011. The most 
common adverse reactions (≥25%) in metastatic BC are neutropenia, anemia, 
asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most 
common serious adverse reactions are febrile neutropenia and neutropenia. The most 
common adverse reaction resulting in discontinuation of eribulin is peripheral neuropathy. The 
complete information supporting the safe and effective use of eribulin is found in the current 
version of the US Prescribing Information (43) which represents the reference information for 
this study, as described in the Investigator’s Brochure (44). 
2.4 
Balixafortide Non-Clinical Development Overview 
In vitro, receptor binding studies demonstrated a high affinity of balixafortide for the human 
CXCR4 receptor, as well as a general lack of significant binding to other potential target 
receptors (44). Balixafortide is not cytotoxic and does not elicit any hemolytic activity in human 
blood in vitro (up to a concentration of 100 µM). 
In vitro plasma protein binding of balixafortide is low with averages of 32% (human), 35% 
(mouse) and 32% (rat) (44). Balixafortide is stable in rat, mouse and human plasma in vitro. 
When administered IV to mouse, dog, or monkey, the terminal half-life (t1/2) ranged from 
0.3−1.7 hours. When balixafortide was infused in humans, the t1/2 ranged from 5−9 hours in 
healthy volunteers, and from 7−15 hours in female patients with metastatic BC. Balixafortide 
is not, or only to a very minor extent, metabolized by enzymes present in liver microsomal 
extracts. The average amount of compound that remained after 60 minutes in in vitro assays 
using liver microsomal extracts from humans, mouse, and rats was 93%, 93%, and 94%, 
respectively. An in vitro assessment of the potential of balixafortide to inhibit the major human 
cytochrome P (CYP) 450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, CYP2E1, CYP3A4 and CYP3A5) showed no significant inhibition with any of the 
substrates tested, using a recombinant human enzyme for each reaction. 
Following IV bolus administration of balixafortide, no significant cardiovascular or respiratory 
effects were observed in cynomolgus monkeys except for transient reduction in blood pressure 
(BP) (for approximately 30 minutes) in 1 animal at the high dose level (1.25 mg); tachycardia 
was observed with reduced RR, QT, and corrected QT (QTc) intervals. In some toxicity 
studies, histaminergic-like responses were observed. In addition, no cardiac effect was 
observed in the electrocardiogram (ECG) recordings in the 28-day repeat-dose toxicity study 
in monkeys with balixafortide doses up to 200 mg/kg subcutaneously (SC), nor in the 13-week 
repeat-dose toxicity study in cynomolgus monkeys, where doses up to 135 mg/kg were 
administered by 2-hour IV infusion.  
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Key toxicological findings included changes in hematology endpoints (i.e. increased leukocyte 
counts); these events were expected based on the pharmacology of balixafortide (44). The 
kidney was identified as the target organ in the 28-day and 13-week repeat-dose toxicity 
studies in monkeys. A dose of 200 mg/kg/day SC produced marked tubular vacuolation 
associated with minimal to slight degeneration/necrosis of the renal tubules. The no-observed-
adverse-effect level (NOAEL) in the 28-day monkey study, was considered to be 
50 mg/kg/day, with a corresponding mean plasma maximum concentration (Cmax) of 60.7 mg/L 
and area under the curve (AUC) of 317.8 mg·h/L, corresponding to safety margins of 4-5 fold 
at a human dose level of 5.5 mg/kg. In the 13-week study in cynomolgus monkeys, where 
balixafortide was administered by 2-hour IV infusion for 3 consecutive days per week to 
approximate the clinical dosing regimen, there was a lower frequency of adverse microscopic 
kidney findings than in the 28-day study. The NOAEL was considered to be 45 mg/kg/day, 
due to the presence of adverse moderate renal tubular degeneration/necrosis with evidence 
of ongoing regeneration in a single female who received high-dose balixafortide 
(135 mg/kg/day) in the main phase and who also had high plasma urea and creatinine. The 
mean Cmax at this dose level was 89.3 mg/L and mean AUC was 378 mgh/L, corresponding 
to safety margins of 7.5- and 5-fold respectively at a human dose level of 5.5 mg/kg. 
Nephrotoxicity biomarker analyses revealed balixafortide-related increased urinary clusterin 
levels, following the 3-day dosing cycles at 135 mg/kg/day, that were reversible following the 
non-dosing period. There were no balixafortide effects on the kidney injury molecule-1 (KIM-
1) urine concentration, and there was high intra-animal variability in cystatin C and neutrophil 
gelatinase-associated lipocalin (NGAL) urine concentrations. 
Balixafortide was not mutagenic in in vitro tests, is not phototoxic, does not block the cardiac 
channels human ether-a-go-go-related gene (hERG), voltage gated sodium channel (NaV1.5) 
or voltage gated sodium channel (CaV1.2) at concentrations in excess of 18-fold the mean free 
plasma concentrations in the clinic, and has been assessed to have a low immunogenic 
potential. Toxicity studies in the mouse and the monkey showed no effects of balixafortide on 
reproductive organs (44).  
No specific local tolerance studies have been performed. Local tolerance was assessed as 
part of the 13-week study in monkey (44). The same infusion rate of 0.5 mL/kg/hour was used 
for all groups. The concentration of balixafortide formulation infused in the high-dose group 
was 13.5 mg/mL. Similar microscopic findings were present in animals in the control and in 
the balixafortide-treated groups, with no relationship to the dose level, and were considered 
infusion procedure-related findings, and not related to balixafortide. 
Overall, balixafortide was well tolerated in toxicity studies and showed minimal to marked 
tubular vacuolation in the kidney at high doses (200 mg/kg) in monkeys. No other target organ 
toxicity was observed in the nonclinical test species. Other study findings were confined to 
hypoactivity in the mouse and transient skin reddening (face and scrotum), swelling of the lips 
and genital area and scratching/biting of the face, tail and body in the monkey, effects 
considered to be due, at least in part, to a histamine response which may be mediated through 
activation of mas-related gene X2 receptor (MRGPRX2). In the 13-week study in monkey, 
some animals exhibited signs of dehydration and emesis at 135 mg/kg/day. 
2.5 
Balixafortide Overview of Clinical Studies 
Balixafortide has been investigated in 6 clinical studies that enrolled a total of 330 subjects, of 
which 235 subjects received at least one dose of balixafortide, in doses ranging from 0.01 to 
5.5 mg/kg. There were 3 completed Phase 1 studies exploring the safety, tolerability, and 
pharmacokinetics (PK) of balixafortide (POL-001, POL-003, POL-004) and two completed 
Phase 2 studies to explore safety, tolerability, efficacy and PK/pharmacodynamics in patients 
with multiple myeloma (POL-002) and acute myocardial infarction (POL-006). Additionally, a 
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Phase 1 study with eribulin in metastatic BC has been conducted and interim results are 
described in Section 2.5.1.  
2.5.1 
Phase 1 Study (POL6326-007 – Ongoing at the time of Protocol 
development) 
POL6326-007 is a Phase 1, open-label, non-randomized, dose escalation study of 
balixafortide + eribulin in 56 female patients aged ≥18 years with Stage IV histologically 
confirmed invasive BC and evidence of tumor cell CXCR4 expression, at least one measurable 
lesion according to Response Evaluation Criteria In Solid Tumors (RECIST v1.1) criteria, who 
previously received at least one chemotherapy regimen for metastatic BC, and were eligible 
to receive eribulin as 2nd to 5th line of chemotherapy for metastatic BC treatment. Patients with 
hormone receptor (HR) positive status must have failed at least one endocrine therapy or be 
considered unsuitable for endocrine therapy. 
In the interim analysis for this study, the ORR and CBR in the patients who received the 
highest dose of balixafortide (5.5 mg/kg) + eribulin (1.4 mg/m2), was 38% and 63%, 
respectively, with a corresponding median duration of 4.4 months and 8.1 months, 
respectively. In the Overall Efficacy Population, the ORR and CBR were lower at 30% and 
44%, respectively, with a correspondingly lower median duration of 3.2 months and 7 months, 
respectively, potentially suggesting a dose response. The Kaplan-Meier analysis showed a 
median PFS of 6.2 months (95% CI, 2.9–8.1) and 4.5 months (95% CI, 3.1–5.7) in the 
Expanded Cohort and Overall Efficacy Populations respectively. 
On 4 October 2017, the date on which all patients had reached 12 months post enrolment, the 
1-year survival rate was 62% (95% CI 47−74) for the Overall Efficacy Population and 75% 
(95% CI 53−88) in the Expanded Cohort. On 4 April 2019, the 18-month survival rate was 42% 
in the Overall Efficacy Population and 50% in the Expanded Cohort; the 24-month survival 
rate was 25% in the Overall Efficacy Population and 33% in the Expanded Cohort (45). 
The median mature OS on 4 September 2018 was 16.8 months for the Overall Efficacy 
Population and 18 months for the Expanded Cohort (46). 
Eribulin + balixafortide was shown to be well tolerated, allowing for a long duration of treatment 
in this study. The median duration of treatment for all patients was 105 days (3−504). 
The incidence of most adverse events (AEs) in this study, even at the highest dose of 
balixafortide (5.5 mg/kg), were similar to those reported in other studies for eribulin alone (22, 
23, 47-49): Grade 3/4 neutropenia 41% for balixafortide + eribulin (45−64% reported for 
eribulin alone in the literature), Grade 3/4 leukopenia 9% for balixafortide + eribulin (14−18% 
reported for eribulin alone in the literature), Grade 3/4 peripheral neuropathy 3.6% for 
balixafortide + eribulin (5−8% reported for eribulin alone in the literature), neuropathy of any 
grade 39% for balixafortide + eribulin (27−35% reported for eribulin alone in the literature), 
and no suggestion that these were associated with increasing balixafortide doses.  
AEs leading to treatment discontinuation were reported in 2 (3.6%) patients: fatigue (2.5 mg/kg 
balixafortide + 1.4 mg/m2 eribulin) and peripheral neuropathy (3.5 mg/kg balixafortide + 
1.4 mg/m2 eribulin). Two patients (3.6%) had treatment emergent adverse events (TEAEs) 
reported to have a fatal outcome: septic shock following neutropenia and streptococcal 
pneumonia in a 55 year old patient receiving 1 mg/kg balixafortide + 1.4 mg/m2 eribulin, and 
neutropenia (Grade 4) and infiltration of both lungs, suggestive of bilateral pneumonia, in a 
48 year old patient receiving 5.5 mg/kg balixafortide + 1.4 mg/m2 eribulin.  
The combination of balixafortide + eribulin demonstrated encouraging signs of activity in 
patients with HER2 negative metastatic BC; the results showed that the safety and tolerability 
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of balixafortide + eribulin was similar to that of eribulin monotherapy in BC or to balixafortide 
monotherapy in studies of healthy volunteers or patients with other malignancies (41). 
The PK profile of balixafortide was not affected by eribulin. Over the entire dose range tested 
for balixafortide, the Cmax and AUC for eribulin were within published ranges (50). Therefore, 
a drug interaction between eribulin and balixafortide is unlikely (51).  
2.5.2 
Balixafortide Population Pharmacokinetics 
The population PK of balixafortide was established using data from 6 clinical studies 
(POL-001, POL-002, POL-003, POL-004, POL-006, and POL6326-007) with a total of 229 
subjects to whom doses ranging from 0.01−5.5 mg/kg were administered as 1-, 2-, or 3-hour 
IV infusions as single or repeated daily doses.  
Using data from all 6 clinical studies, the population PK analysis of balixafortide estimated a 
clearance (CL) of 6.5 L/h, a total volume of distribution (Vz) of 45 L, and a t1/2 of 6.6 h for a 
typical healthy individual. In the metastatic BC patient population, CL was lower (4.4 L/h), Vz 
larger (49 L), and terminal t1/2 longer (16 h). Balixafortide PK was non-linear with a faster CL 
at low doses. The between patient variability was moderate with a coefficient of variation for 
balixafortide CL of 20%. Estimated glomerular filtration rate (GFR) was a statistically 
significant covariate of CL, with slower CL in individuals with a reduced estimated GFR. There 
was a larger Vz and a faster CL in heavier individuals. There was a larger peripheral volume 
and a faster inter-compartmental exchange in older individuals. 
2.6 
Balixafortide Current Benefit/Risk Ratio 
Balixafortide is being developed in combination with eribulin for the treatment of HER2 
negative, locally recurrent metastatic BC, in adult patients who have progressed after at least 
one chemotherapeutic regimen for advanced disease. Prior therapy should have included an 
anthracycline and a taxane unless contra-indicated for safety reasons. In this protocol, locally 
recurrent BC is defined as unresectable locoregionally recurrent BC. 
The safety profile of balixafortide is derived from 6 clinical studies (three Phase 1, one 
Phase 1/2 and two Phase 2 studies) that enrolled a total of 330 subjects, of which 235 subjects 
received at least one dose of balixafortide, either as a single agent or in combination with other 
drugs (44). The IV formulation was investigated in a broad range of doses from 
0.01−5.5 mg/kg, with IV infusion times between 1 and 3 hours, and treatment duration up to 
16 months. The accumulated safety data for balixafortide and the known safety profile of 
eribulin indicates that the following AEs of special interest (AESIs) should be evaluated and 
managed in accordance with established guidelines (e.g. American Society of Clinical 
Oncology [ASCO] guidelines for minimizing the incidence of febrile neutropenia): 
hypersensitivity/infusion-related reaction (IRRs), neutropenia, febrile neutropenia, infections 
associated with neutropenia, and renal impairment. The following AEs of particular interest 
(AEPIs) should be evaluated and managed: thrombocytopenia, QTc interval prolongation, 
peripheral neuropathy and hepatic impairment. Detailed information is provided in this protocol 
and the accompanying Investigator’s Brochure. 
In the Phase 1 study POL6326-007 (Section 2.5.1), the combination of balixafortide + eribulin 
demonstrated encouraging signs of activity in patients with HER2 negative metastatic BC, and 
the results showed that the safety and tolerability of balixafortide + eribulin was similar to that 
of eribulin or balixafortide monotherapy (41). This supports a positive benefit-risk balance in 
the target population, which is designed to reasonably reflect the target population in clinical 
practice.  
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Based on the available efficacy and safety data for balixafortide, the benefit risk profile remains 
unchanged and favorable. Further development of balixafortide in combination with eribulin, 
is justified by the anticipated benefits expected for patients with HER2 negative, locally 
recurrent or metastatic BC, who have progressed after at least one chemotherapeutic regimen 
for advanced disease. 
2.7 
Conduct of Study 
This clinical study will be conducted in compliance with this Protocol, the Good Clinical 
Practice (GCP) guidelines of International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH), US Food and Drug Administration 
(FDA) GCP Regulations: Code of Federal Regulations (CFR) Title 21, parts 11, 50, 54, 56, 
and 312 as appropriate, EU Directive 2001/20/EC and Commission Directive 2005/28/EC and 
EC ENTR/CT2, the guidelines of the World Medical Association Declaration of Helsinki in its 
revised edition (Fortaleza, Brazil, 2013), the General Data Protection Regulation (EU) 
2016/679, designated Standard Operating Procedures (SOPs), and with local laws and 
regulations relevant to the use of new therapeutic agents in the country of conduct. 
In this study, the Investigator can delegate his/her tasks to an appropriately qualified designee. 
In this study, the use of the term Sponsor also refers to the Sponsor's designee. 
3. 
STUDY DESIGN 
3.1 
Scientific Rationale for Study Design 
Current treatment options for patients with locally recurrent and metastatic BC who have failed 
at least one chemotherapeutic regimen for advanced BC are modestly effective, strengthening 
the medical need for more therapeutic options with demonstrable improvement in clinical 
outcomes while not adding significantly to cumulative toxicity for patients with metastatic, 
HER2 negative BC. 
Balixafortide is a potent, selective antagonist of the CXCR4 which has a central role in the 
progression of metastatic BC (13). Eribulin has regulatory approval in the US and in a number 
of other countries for treatment of patients with advanced BC who have failed at least two 
chemotherapeutic regimens for metastatic disease and in the EU for treatment of patients with 
advanced BC who have failed at least one chemotherapeutic regimen for metastatic disease.   
The novel combination of balixafortide with eribulin is intended to improve disease control 
(reduce tumor burden and/or provide a period of disease stabilization) in patients with HER2 
negative, locally recurrent or metastatic BC.  
Phase 1 clinical data (Study POL6326-007), as well as nonclinical data, have provided 
meaningful information to support the pharmacology, safety profile and dose of balixafortide, 
and eligibility for enrolment, choice of reference therapy, and objectives for this Phase 3 trial.  
The interim results of the Phase 1 trial (POL6326-007) in patients with relapsed metastatic BC 
provide highly promising results with regard to the efficacy and the overall safety profile of 
balixafortide in combination with eribulin. This supports a positive benefit-risk balance in the 
target population, which is designed to reasonably reflect the target population in clinical 
practice.  
To address concerns of potential bias in assigning subjects to study drugs (selection bias), a 
central randomization procedure will be used. To address concerns of potential bias in the 
evaluation of patients (assessment bias), blinded centralized review of computed tomography 
(CT)/magnetic resonance imaging (MRI) scans have been included in the design of this 
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Phase 3 study to allow an unbiased estimate of the size of effect to be obtained. The study 
endpoints for this pivotal Phase 3 study are well recognized and accepted standards for 
evaluating the efficacy of oncology treatments.  
In order to protect the integrity of the trial and the robustness of the results, project team 
members (both Polyphor Ltd and Contract Research Organization [CRO] personnel) will not 
evaluate, formally or informally, data grouped by randomized treatment arm as data are 
accruing over time; the exception to this will be the pre-planned interim efficacy analyses and 
safety reviews. Procedures relating to the execution of pre-planned interim efficacy analyses 
and safety reviews by the Data Safety Monitoring Committee (DSMC) are described in the 
DSMC charter. Procedures for the coding/blinding of the patient’s name/identity for the 
Independent Review Committee (IRC) is provided in the imaging plan.  
Regular monitoring of Investigators by Sponsor-designated personnel, instruction manuals, 
and data verification (including cross-checking and data audits) will be performed to ensure 
the quality of all data. 
3.2 
Justification for Dose  
The dose of balixafortide to be used in this study (5.5 mg/kg) and the frequency of its 
administration have shown promising results with regard to efficacy, safety and tolerability in 
study POL6326-007 (Section 2.5.1). In study POL6326-007, no dose-limiting toxicities were 
confirmed and, therefore, the maximum tolerated dose was not reached. The highest 
balixafortide dose evaluated in this study was 5.5 mg/kg. Dosing to maximum tolerated dose 
was not continued because, based on PK evaluation, further dose increments by 1 mg/kg 
balixafortide (the maximum increment allowed in the protocol) would not have provided a 
sufficient increase in exposure; in addition, the ORR observed in Part II of this study was 3-
fold greater than that published for eribulin alone. This suggested that anti-tumor activity was 
worthy of further exploration at the 5.5 mg/kg dose which was selected as the recommended 
Phase 2 dose.    
Patients will receive eribulin mesylate at the dose approved in both the US and the EU 
(1.4 mg/m2), with the appropriate dose reductions as described in Section 6.1.2. Eribulin is 
approved for use on Days 1 and 8 of each treatment cycle; however, in this study eribulin will 
be administered on Days 2 and 9 of each treatment cycle to allow balixafortide treatment to 
begin before eribulin. This cycle scheme was also used in study POL6326-007, and the 
schedule was designed to maximize exposure to balixafortide in relation to eribulin, while 
minimizing the number and burden of balixafortide administrations for the patient. In addition, 
this regimen allows for significant disruption of the protective tumor microenvironment (e.g. 
blockade of pro-survival SDF-1 signalling, change in the distribution and activation of 
immunosuppressive cells) by balixafortide in combination with eribulin. Bracketing the 
administration of balixafortide with chemotherapy is deemed appropriate regardless of 
whether a synergistic or immune-stimulant effect is the pharmacodynamic driver of 
balixafortide.  
3.3 
Overall Design 
This international, multicenter, open-label, randomized, parallel, two-arm, pivotal Phase 3 trial 
has been designed to investigate the efficacy and safety of balixafortide in combination with 
an established, approved therapy (eribulin) relative to eribulin monotherapy in patients with 
HER2 negative, locally recurrent or metastatic BC who have previously been treated with 1−4 
chemotherapeutic regimens for locally recurrent or metastatic BC. Unless contra-indicated for 
safety reasons, patients will have previously received an anthracycline and a taxane in either 
the adjuvant or metastatic setting. In this protocol, locally recurrent BC is defined as 
unresectable locoregionally recurrent BC. 
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Two populations of patients will be studied, the: 
• 
Overall Population, who receive study medication as 2nd to 5th line of therapy, which 
will constitute the primary population for regulatory submissions in the EU and 
jurisdictions in which the 2nd line + eribulin label applies. 
• 
3rd line + population, who receive study medication as 3rd to 5th line of therapy 
(3rd line +), which will constitute the primary population for regulatory submissions in 
the US and jurisdictions in which the 3rd line + eribulin label applies. 
 
Patients will be stratified according to: 
• 
Line of therapy (2nd line versus 3rd line +) for locally recurrent or metastatic BC.  
• 
HR status (positive versus negative) based on ER or progesterone receptor (PgR) 
status. 
• 
Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment received previously (received a 
CDK 4/6 inhibitor previously versus not received a CDK 4/6 inhibitor previously). 
• 
Visceral versus non-visceral disease. Visceral metastases will include brain, 
pulmonary, pleural, hepatic and peritoneal involvement (including pleural effusions and 
ascites). Any other sites of metastases (e.g. bone, lymph nodes, and skin) will be 
considered to be non-visceral. Patients with visceral metastases, irrespective of the 
presence of any other metastatic sites (e.g. bone), will be categorized as visceral. All 
other patients without visceral metastases will be categorized as non-visceral. 
 
The study will consist of the following:  
• 
Screening Assessments: To be obtained ≤21 days prior to randomization. 
• 
Randomization: Patients will be randomized within 21 days of starting screening and 
after having completed the required screening assessments. Patients will be 
randomized either to the balixafortide + eribulin treatment arm or to the eribulin 
treatment arm. All patients must begin treatment within 3 days after randomization.  
• 
Treatment Phase: The treatment regimens for the study are described in 
Section 6.1.1. Patients will receive 21-day cycles of treatment. All patients will receive 
eribulin on Days 2 and 9 of each cycle (the rational for this frequency is explained in 
Section 3.2). In addition, patients randomized to the balixafortide + eribulin arm will 
receive balixafortide on Days 1−3 and Days 8−10 of each cycle.  
Response Assessments During Treatment: From the date of randomization, patients 
will be evaluated according to RECIST v1.1 for complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease (PD) based on CT/MRI 
scans performed every 6 weeks (±7 days) during the first year, and then performed 
every 12 weeks (±7 days), thereafter, until PD is documented by RECIST v1.1. At the 
discretion of the Investigator, additional radiographic tumor assessments may be done 
at any time if there is clinical suspicion of disease progression. The decision about the 
patient’s disease status and progression during the study will be taken based on the 
local radiologist’s/Investigator’s assessment. 
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From the date of randomization, additional bone scans will be performed at the 
discretion of the Investigator (e.g. to confirm CR, to follow up existing metastases, or 
if [based on signs and symptoms] new bone metastases are suspected). 
It is critical that tumor assessments are performed according to the Study Schedule in 
a timely and complete manner to allow full comparability of the two treatment arms. To 
prevent the introduction of any bias into the efficacy results, the assessment must be 
performed according to the calendar regardless of any dosing delay or interruption. 
Imaging assessments will be scheduled using the randomization date as the reference 
date for all timepoints and NOT scheduled according to the date of the previous 
imaging timepoint. A delay in the imaging assessment to accommodate a treatment 
delay is not permitted. Incomplete assessment and/or wrong timing (out of Schedule) 
will result in the inability to accurately assess disease status for that timepoint. For a 
given patient/tumor lesion, the same technique for tumor assessment MUST be used 
throughout the study.  
Following initial documentation of an objective response, a confirmatory CT/MRI scan 
will be performed at least 4 weeks later. 
Patients will continue treatment as assigned at randomization, until objective PD 
(according to RECIST v1.1) is documented, there is unacceptable toxicity, death 
occurs, the patient withdraws consent, or the patient is lost to follow-up (whichever 
occurs first). 
Patients who progress radiologically according to RECIST v1.1, but who are deemed 
by the Investigator to be clinically benefiting from study medication, may continue that 
study medication at the discretion of the Investigator; a PD confirmatory scan will be 
done at least 6 weeks after the last scan to identify potential pseudo-progression.  
Patients discontinued from treatment, for reasons other than PD, will enter the PD 
Follow-up (as described in PD Follow-up below) unless death occurs, the patient 
withdraws consent to efficacy follow-up, or the patient is lost to follow-up.   
• 
End-of-Treatment (EoT) Evaluation: This will occur as soon as possible, within 
7 days after discontinuation of study medication and prior to initiation of any new anti-
cancer therapy, regardless of the reason for discontinuation. A targeted physical 
examination will be conducted. Weight, Eastern Cooperative Oncology Group (ECOG) 
performance status, AEs, vital signs, clinical laboratory tests, 12-lead ECG and 
concomitant medications will be assessed and recorded for all patients at this visit. 
Patients who are discontinued from study medication for any reason, in the absence 
of objective PD (according to RECIST v1.1), will undergo tumor response assessment. 
For patients at selected sites, an optional tumor biopsy will be performed. Patients will 
complete quality of life (QoL) questionnaires. 
• 
30-Day Safety Follow-up: This will occur 30 days (and no later than 37 days) from 
the last dose of study drug. AEs will be assessed and recorded for all patients at this 
visit. Concomitant medications will also be recorded for patients with unresolved AEs. 
• 
Long-term Follow-up:  
(i) PD Follow-up: Regardless of treatment arm, patients who are discontinued from 
study medication for any reason  in the absence of PD, will undergo repeat imaging 
and tumor response assessments (including CT/MRI scans) every 8 weeks 
±7 days (every 12 weeks ±7 days if the patient has been on the study for ≥1 year) 
until PD is documented as per RECIST v1.1, or death occurs, or patient is lost to 
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follow-up, or the patient withdraws consent (whichever occurs first). If a patient 
stops study medication and begins other anti-cancer therapy before PD is 
documented, every effort should be made to perform tumor evaluation in these 
patients until disease progression. 
(ii) Survival Follow-up: The Investigator will monitor the patient for OS status every 
6 months (or more frequently) until death, until the patient withdraws consent to 
follow-up for survival, or until the patient is lost to follow-up (whichever occurs first). 
(iii) Every effort should be made to collect and record all anti-cancer medicines that 
the patient receives during Long-term Follow-up in the patient's source data and 
electronic case report form (eCRF) until the end of study.  
 
In this study, 384 patients will be enrolled (192 patients in the balixafortide + eribulin treatment 
arm, and 192 patients in the eribulin treatment arm) including 320 patients who will receive 
study medication as 3rd line +.  
Patients will undergo assessment for:  
• 
Efficacy. 
• 
Safety and tolerability. 
• 
PK (including metabolites). 
• 
Immunogenicity. 
• 
QoL. 
• 
Exploratory biomarkers (including interferon [IFN]-gamma and other circulating 
cytokines).  
At selected sites, the study will include assessment of additional exploratory blood and tissue 
biomarkers. 
The Study Schedule of Assessments and sampling are outlined in Section 1.1.  
3.4 
Randomization and Treatment Allocation 
Patients will be randomized in a 1:1 ratio to one of the following treatment regimens: 
• 
Balixafortide + eribulin treatment arm 
or 
• 
Eribulin treatment arm.  
 
Patients will be stratified as described in Section 3.3. CXCR4 expression (high versus low; 
threshold to be determined) is not currently planned as a stratification factor since (i) there is 
currently no validated test, and (ii) there was no correlation of ORR/CBR with level of CXCR4 
expression in the Phase 1 trial. That said, CXCR4 expression level, based on 
immunohistochemistry (IHC) of historical tumor samples, will be recorded and the correlation 
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with efficacy will be explored. It should be noted that all BC patients screened for the Phase 1 
trial expressed CXCR4 to some degree. 
Both the randomization and the stratification will be handled by an Interactive Response 
System (IRT); refer to the IRT manual for further details.   
4. 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Primary Objective 
The primary objective of this study is: 
• 
To evaluate the efficacy of balixafortide + eribulin versus eribulin monotherapy on (i) 
PFS in the Overall Population and (ii) PFS and ORR in the 3rd line + population.  
4.2 
Secondary Objectives  
The secondary objectives of this study are: 
• 
To compare the OS between patients in the balixafortide + eribulin treatment arm 
versus eribulin monotherapy treatment arm. 
• 
To compare measures of tumor response between patients in the balixafortide + 
eribulin treatment arm versus eribulin monotherapy treatment arm. 
• 
To evaluate the safety and tolerability of balixafortide + eribulin versus eribulin 
monotherapy. 
4.3 
Exploratory Objectives  
The exploratory objectives of this study are: 
• 
To determine whether the treatment outcome correlates with baseline ER, PgR, or 
CXCR4 expression level. 
• 
To assess tumor tissue and circulating biomarkers and possible association with 
patient treatment outcome. 
• 
To explore immune response as assessed by iRECIST. 
• 
Measurement of plasma concentration of balixafortide and potential metabolites to 
integrate in a population PK model.  
• 
To assess the QoL as reported by patients in the balixafortide + eribulin treatment arm 
versus eribulin monotherapy treatment arm using standard QoL assessments. 
4.4 
Endpoints 
4.4.1 
Overall Population Efficacy Endpoints 
Primary Efficacy Endpoint 
In the Overall Population intended for regulatory submissions in the EU and jurisdictions in 
which the 2nd line + eribulin label applies, the primary endpoint is:  
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• 
PFS according to RECIST v1.1 guidelines, as assessed by the IRC.  
 
Key Secondary Efficacy Endpoint 
• 
OS. 
The statistical design in the overall, 2nd line+ population, with pre-defined alpha allocation and 
recycling, is such that if PFS does not meet statistical significance at its allocated alpha level, 
then the design still allows OS to be tested and, if it meets statistical significance at its allocated 
alpha level, then the study can still be formally positive for efficacy.  
 
Other Secondary Efficacy Endpoints 
• 
PFS according to RECIST v1.1 guidelines, as assessed by the local Investigator's 
review. 
• 
ORR [confirmed CR + confirmed PR]) according to RECIST v1.1 guidelines, as 
assessed by the IRC in the Overall Population.  
• 
ORR (confirmed CR + confirmed PR) according to RECIST v1.1 guidelines, as 
assessed by the local Investigator's review. 
• 
CBR (proportion of patients with confirmed CR, confirmed PR, or SD ≥6 months) 
according to RECIST v1.1 guidelines as assessed by the IRC and by the local 
Investigator's review. 
• 
Disease control rate (DCR; number of patients with confirmed CR, confirmed PR, or 
SD) according to RECIST v1.1 guidelines as assessed by the IRC and by the local 
Investigator's review. 
• 
Time to response as assessed by the IRC and by the local Investigator's review. 
• 
Duration of response as assessed by the IRC and by the local Investigator's review. 
4.4.2 
3rd Line + Population Efficacy Endpoints 
Co-Primary Endpoints 
In the 3rd line + population intended for regulatory submissions in the US and jurisdictions on 
which the 3rd line + eribulin label applies, the co-primary endpoints are:  
• 
ORR (confirmed CR + confirmed PR) according to RECIST v1.1 guidelines, as 
assessed by the IRC.  
• 
PFS according to RECIST v1.1 guidelines, as assessed by the IRC.  
If PFS in the 3rd line + population is met at the allocated alpha level, PFS in the Overall 
Population will also be formally tested at the same alpha level. 
Key Secondary Efficacy Endpoint 
• 
OS.  
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The statistical design in the 3rd line + population, with pre-defined alpha allocation and 
recycling, is such that even if ORR does not meet statistical significance at its allocated alpha 
level, then PFS can still be tested and, if it meets statistical significance at its allocated alpha 
level, the study can still meet its primary objective. Further, if PFS does not meet statistical 
significance at its allocated alpha level, then OS can still be tested and, if it meets statistical 
significance at its allocated alpha level, then the study can still be formally positive for efficacy.  
 
Other Secondary Efficacy Endpoints 
• 
PFS according to RECIST v1.1 guidelines, as assessed by the local Investigator's 
review. 
• 
ORR (confirmed CR + confirmed PR) according to RECIST v1.1 guidelines, as 
assessed by the local Investigator's review. 
• 
CBR (proportion of patients with confirmed CR, confirmed PR, or SD ≥6 months) 
according to RECIST v1.1 guidelines as assessed by the IRC and by the local 
Investigator's review. 
• 
DCR (number of patients with confirmed CR, confirmed PR, or SD) according to 
RECIST v1.1 guidelines as assessed by the IRC and by the local Investigator's review. 
• 
Time to response as assessed by the IRC and by the local Investigator's review. 
• 
Duration of response as assessed by the IRC and by the local Investigator's review. 
4.4.3 
Secondary Safety Endpoints 
These will include: 
• 
Type, frequency and severity of AEs (including serious adverse events [SAEs], AESIs). 
• 
Laboratory abnormalities. 
• 
Vital signs. 
Additionally, signs and symptoms of anaphylaxis will be captured and summarized in 
accordance with guidance provided by the Second Symposium on the Definition of 
Anaphylaxis (52). Evaluation of liver parameters will be made according to the evaluation of 
Drug-induced Serious Hepatotoxicity (eDISH) criteria (53); this requires a log-log plots of 
alanine aminotransferase (ALT)/aspartate aminotransferase (AST) vs total bilirubin to identify 
potential cases of concern, followed by time course plots of all the identified potential cases.  
4.4.4 
Exploratory Endpoints 
• 
Relationship between objective response, PFS, or OS and ER, PgR or CXCR4 
expression levels. 
• 
Relationship between objective response, PFS, or OS and exploratory biomarkers 
(from tumor tissue or blood) including cytokines (e.g. IFN-gamma), immune cells 
profile, and ribonucleic acid (RNA) expression. 
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• 
Response as assessed by iRECIST (2017) in those patients who continue treatment 
despite progression. 
• 
Plasma concentration of balixafortide and potential metabolites (Population PK).  
• 
European Organization for the Research and Treatment of Cancer Quality of Life 
Questionnaire (EORTC-QLQ-C30) change from baseline to the end of each treatment 
cycle. 
• 
The Functional Assessment of Cancer Therapy Breast (FACT-B) and EuroQol-5D 
(EQ-5D) change from baseline to the end of each treatment cycle. 
5. 
STUDY POPULATION 
5.1 
Patient Inclusion Criteria 
Patients with measurable and non-measurable disease will be eligible for inclusion in this 
study only if all the following criteria are met:  
1. Patients at least 18 years of age (or according to local regulation). 
2. Documented histologically confirmed BC. 
3. Metastatic BC currently of stage IV disease by American Joint Committee on Cancer 
criteria or unresectable locoregionally recurrent BC. 
4. Molecular status and prior therapies: 
a) Molecular Status 
Eligible patients are, by their patient records and prior therapy, HER2 negative 
with any ER or PgR status. If a previous record of the HR status is not available, 
the HR status should be tested locally.   
HER2 negative (IHC 0,1 or fluorescence in situ hybridization [FISH] or 
chromogenic in situ hybridization [CISH] HER2:CEP17 ratio < 2.0); HER2 2+ 
patients should be FISH/CISH negative. 
b) Prior Therapies 
Patients with locally recurrent or metastatic BC who have previously received 1−4 
chemotherapeutic regimens for the treatment of locally recurrent or metastatic BC. 
Unless contra-indicated for safety reasons, prior therapy will have included an 
anthracycline and a taxane in either the adjuvant or metastatic setting. 
Patients with HR positive status (ER+ and/or PgR+) must have been treated with 
at least one line of endocrine therapy and considered by the treating physician not 
to be a candidate for further endocrine therapy. 
5. At least 14 days from the completion of any previous cytotoxic chemotherapy, biological 
therapy, or any other investigational agent at time of initiation of study medication. 
Resolution of chemotherapy and radiation therapy related toxicities to Grade 1 or lower 
severity, except for stable sensory neuropathy Grade 2 or lower and alopecia. 
6. Patients must have proved refractory to the most recent chemotherapy, documented by 
progression on or within six (6) months of therapy. 
7. Females of child bearing potential must be willing and able to use highly effective 
contraception (as described in the protocol) whilst they or their male partners are on this 
study from randomization until 3 months after the last dose of study medication 
(Section 5.4.5). Male patients must commit to using an approved form of birth control 
(including double-barrier contraception [e.g. consistent and correct use of male condom 
with diaphragm or male condom with cervical cap] or sterilization method) while on 
treatment and for 3 months after the last dose of study medication (Section 5.4.5).    
8. ECOG performance status of 0-2. 
9. Life expectancy of 3 months or more as per Investigator assessment. 
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10. Adequate organ function defined at Screening as: 
a) WBC ≥3000/mm3 
b) Absolute neutrophil count (ANC) ≥1500/mm3.  
c) Platelets ≥75000/mm3*. 
d) Creatinine Clearance ≥30 mL/minute as calculated by the Cockcroft-Gault equation 
or serum creatinine <1.5x institutional upper limit of normal (ULN) (2). 
e) Total bilirubin ≤1.5x institutional ULN; AST, ALT ≤3x institutional ULN (for patients 
with liver metastases, ≤5x ULN). 
f) Hemoglobin ≥10 g/dL. 
11. Patients who have central nervous system involvement if metastases have been treated 
and are stable for at least 4 weeks after completion of radiation therapy and/or surgery. 
Stable is defined as the absence of the need for dexamethasone or other corticosteroid 
therapy, and radiographic confirmation of SD.  
12. Patients receiving bone-modifying agents (BMA [bisphosphonates or denosumab]) if BMA 
was initiated at least 4 weeks prior to the start of study medication. 
13. Must be willing and able to comply with the protocol and must understand and sign an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent document. 
14. Affiliation with a National Health Insurance plan (applicable to patients in France only). 
 
* ≥100000/mm3 in France 
 
5.2 
Patient Exclusion Criteria 
Patients will be ineligible if one or more of the following statements are applicable: 
1. Previously received eribulin. 
2. Peripheral neuropathy Grade ≥3. 
3. Receipt of prior CXCR4 therapy. 
4. Receipt of colony stimulating factors (CSFs) filgrastim, pegfilgrastim, or sargramostim 
within 14 days prior to time of initiation of study medication. 
5. Radiation therapy within 14 days prior to time of initiation of study medication. 
6. Severe concurrent illness or psycho-social situation that would limit compliance with 
study requirements or that, in the Investigator’s opinion, would preclude enrolment. 
7. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to balixafortide or eribulin, or known intolerance to balixafortide or eribulin. 
8. Breast feeding or pregnant, as determined by a serum pregnancy test beta human 
chorionic gonadotrophin (β-HCG) at Screening and prior to the administration of study 
medication. 
9. Patients with congestive heart failure, electrolyte abnormalities, bradyarrhythmias, 
known congenital long QT syndrome, QT interval corrected with Fridericia's formula 
(QTcF) ≥470 milliseconds (msec) at baseline in the absence of bundle branch block, or 
currently taking drugs at known risk of prolonging the QT interval or causing torsades de 
pointes (TdP) (including Class Ia and III anti-arrhythmic drugs; see also Appendix 1 
Prohibited Medications). Patients with hypokalemia or hypomagnesemia should not be 
randomized until the hypokalemia or hypomagnesemia is corrected. 
10. Patients with a concurrent malignancy or malignancy 2 years prior to randomization with 
the exception of adequately treated basal and squamous cell carcinoma, non-
melanomatous skin cancer, or curatively resected cervical cancer. 
11. Persons who have been housed in an institution due to a government or judicial order 
(applicable to Germany only). 
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5.3 
Patient Withdrawal Criteria 
5.3.1 
Discontinuation from Treatment 
The term "treatment interruption" refers to a patient stopping the study drug during the course 
of the study, but then re-starting it at a later time in the study (see Section 6.1). The reason for 
dosing interruption will be collected on the patient’s source data and eCRF. 
The term "treatment discontinuation" refers to a patient's withdrawal from the study treatment 
phase. The reason for discontinuation from treatment will be collected on the patient’s source 
data and eCRF. 
Treatment discontinuation should be discussed where possible with the Sponsor before the 
patient stops treatment with the study medication, and the Study Monitor should be notified 
before treatment discontinuation.  
Patients may be discontinued from treatment in case of: 
• 
Disease progression according to RECIST v1.1. However, patients are allowed to 
continue on treatment based on medical judgement. 
• 
Deterioration in the general health status of the patient without evidence of disease 
progression according to RECIST v1.1. 
• 
Unacceptable toxicity or AE. 
• 
Pregnancy (Section 5.3.4). 
• 
Patient withdraws consent to continue treatment.  
 
Patients who discontinue study medication for any reason should not be considered as 
discontinued from study (Section 5.3.2); these patients should be requested to attend the EoT 
visit, the 30-day Safety Follow-up visit and the Long-term Follow-up visits as outlined in the 
Study Schedule (Section 1.1), unless consent to participate in the study and consent to be 
followed for OS is also withdrawn (Section 5.3.3). 
5.3.2 
Discontinuation from Study  
The term “study discontinuation” refers to a patient’s withdrawal from the study, including 
treatment discontinuation (if the patient is still on treatment) as well as the 30-Day Safety 
Follow-up and Long-term Follow-up.  
Patients are discontinued from study in case of: 
• 
Withdrawal of full consent (Section 5.3.3). 
• 
At the discretion of the Investigator, for instance, for safety reasons. 
• 
Death. 
• 
Lost to follow-up. 
Reasonable effort should be made and documented to contact any patient lost to follow-up 
during the study in order to complete assessments and retrieve any outstanding data. One 
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documented attempt must include sending a certified letter to the patient’s last known address, 
requesting that they return to the study site for final evaluations. If necessary, the patient's 
family doctor/general practitioner will be contacted for collection of survival data. 
If a patient withdraws consent to continue with the study, no further evaluations will be 
performed, and no additional data should be collected. The Sponsor may retain and continue 
to use any data collected before such withdrawal of consent in compliance with local laws and 
regulations.  
5.3.3 
Patient Withdrawing Consent 
Patients will be advised on the Informed Consent Form (ICF) that at any time, for any reason, 
without prejudice, they have the right to withdraw consent to: 
(i) Treatment only, but still consent to post-treatment study visits and Long-term Follow-
up (for PD and survival). 
(ii) Treatment and to post-treatment study visits, but consent to Survival Follow-up. 
(iii) Treatment, post-treatment study visits and Long-term Follow-up (i.e. discontinuation 
from study). 
5.3.4 
Patient Withdrawal in case of Pregnancy 
Patients who become pregnant during the study must be withdrawn from treatment 
immediately. 
In the event of a pregnancy, whenever possible, it should be followed to term, any premature 
terminations reported to the Sponsor, and the status of the mother and child should be 
reported to the Sponsor after delivery and at important developmental milestones during the 
first year (Section 9.3). 
5.3.5 
Patient Replacement 
Patients who discontinue from treatment or study will not be replaced. 
5.4 
Patient Restrictions 
5.4.1 
Prior or Concomitant Medication 
Patients must be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with the Investigator. Any medications, 
including herbal supplements, vitamins, or treatment taken by the patient, from 28 days prior 
to the start of study medication and up to 30 days (and no later than 37 days) following the 
last dose of study drug (as described in Section 7.7) and the reason for their administration 
must be recorded on the patient’s source data and eCRF. 
Routine postoperative care, such as dressing changes, suture removal, drain removal, does 
not need to be recorded. Anesthetics used for any surgical procedures performed during the 
patient’s participation in the study can be recorded as “unspecified anesthesia” on the 
concomitant treatment records; it is not necessary to list the specific anesthetics. Palliative 
and supportive care for cancer-related symptoms can be used and must be recorded in the 
patient’s source data and eCRF. 
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5.4.2 
Permitted Medications 
The following are permitted throughout the duration of the treatment: 
• 
Standard therapies for pre-existing medical conditions, medical and/or surgical 
complications, and palliation may be used during this study. Any medication intended 
solely for supportive care (e.g., analgesics, antidiarrheals, antidepressants) may also 
be used at the Investigator’s discretion. All medications must be recorded in the 
patient’s source data and eCRF. 
• 
Antihistamines (H1 receptor antagonists) and corticosteroids can be used to 
manage IRRs Section 9.2.6.3). At the discretion of the treating physician, H1 receptor 
antagonists may be used as premedication for the prevention of IRRs.  
• 
Hematopoietic growth factors (e.g., granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage colony stimulating factor [GM-CSF]): Receipt of CSFs within 
14 days prior to study Day 1 (Cycle 1) are not permitted (Section 5.2). However, after 
study Day 1 (Cycle 1), this study requires adherence to the ASCO guidelines for 
minimizing the incidence of febrile neutropenia, including the recommended 
prophylactic use of CSFs, where appropriate at the discretion of the Investigator 
(Appendix 7 ASCO Guidance on the Use of CSFs) (54). Risk factors for febrile 
neutropenia in addition to those posed by eribulin and advanced BC are shown in 
Table 10.  
• 
Erythropoietin may be used at the Investigator's discretion for the supportive 
treatment of anemia. 
• 
Bisphosphonates may be continued for the treatment of osteoporosis or 
management of existing bone metastases for patients who have been receiving them 
at a stable dose for at least 4 weeks prior to randomization (Section 5.1). If the dose is 
increased or therapy is initiated during the study, the reason must be documented in 
the patient source documentation and disease progression according to RECIST v1.1 
must be ruled out. 
• 
Palliative radiotherapy is permitted if done solely for bone pain relief. If palliative 
radiotherapy is initiated after start of study medication, the reason for its use must be 
clearly documented and disease progression according to RECIST v1.1 must be ruled 
out. 
5.4.3 
Prohibited Medications 
Anti-cancer agents: No additional investigational or commercial anti-cancer agents such as 
chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or endocrine 
therapy other than eribulin and balixafortide will be permitted during the study treatment phase. 
Patients who receive any other drug which is indicated for the treatment of BC during the 
treatment phase will be withdrawn from treatment and will be requested to attend the EoT visit 
and the 30-day Safety Follow-up visit. The Investigator will also follow these patients for PD 
and survival (Long-term Follow-up). 
Drugs at known risk of prolonging the QT interval or causing TdP are prohibited during 
the study treatment phase. A list of prohibited drugs is provided in Appendix 1 Prohibited 
Medications. If the patient is on treatment with a drug at known risk of prolonging the QTc 
interval or causing TdP, an alternative medication should be considered. If an alternative is 
not available or deemed appropriate, the patient should be excluded from participation in the 
study. 
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5.4.4 
Medications Not Recommended 
The following treatments are not recommended throughout the duration of the study treatment 
phase. Alternative therapies should be considered whenever possible. If usage of the following 
treatments is deemed necessary, consultation and agreement with the Sponsor is required 
prior to treatment initiation. 
Chronic immunosuppressive therapies and/or high dose steroids should be avoided, 
including systemic corticosteroids. Steroids given for physiological replacement, as anti-
emetics, or inhaled as well as short course of oral/topical or short acting steroids given for 
allergic reactions or asthma flares are allowed. Corticosteroids can be used to manage IRRs 
during the study (Section 9.2.6.3). 
The use of herbal medicines is not recommended during the study treatment phase. 
5.4.5 
Women and Men of Child bearing Potential 
A woman is considered to be of child bearing potential unless she meets at least one of the 
following criteria: 
• 
Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy. 
• 
Premature ovarian failure confirmed by a specialist. 
• 
XY genotype, Turner syndrome, uterine agenesis. 
• 
Postmenopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition). 
All women of child bearing potential must be instructed to use adequate, highly effective 
contraception whilst they or their male partners are taking part in this study from randomization 
until 3 months after the last dose of study medication. Contraceptive methods should be in 
compliance with local legislation. Such contraception includes: 
• 
Intrauterine devices (IUD)  
• 
Sterilization method (bilateral tubal occlusion or vasectomized partner), 
• 
True abstinence from intercourse with a male partner only when this is in line with the 
preferred lifestyle of the subject. 
Note: hormonal contraception is contra-indicated in women patients participating in 
this study. However, the female partners of male patients participating in this study can 
use hormonal contraception if medically indicated. 
Male patients must be willing to use an approved form of birth-control, including double-barrier 
contraception (e.g. consistent and correct use of male condom with diaphragm or male 
condom with cervical cap) or sterilization method, from randomization until 3 months after the 
last dose of study medication. Male patients are also encouraged to seek advice on 
conservation of sperm prior to beginning study medication because of the possibility of 
irreversible infertility due to therapy with eribulin. The study doctor should discuss acceptable 
birth control options with the patient. The methods of birth control used must be recorded in 
the source data and eCRF. 
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5.4.5.1 Pregnancy Test 
Analysis of samples for pregnancy tests will be conducted locally. For patients of child bearing 
potential, a serum β-HCG pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed at the Screening Visit no more than 7 days prior to Randomization. Before 
beginning dosing for each Cycle (on Study Day 1 for patients on the balixafortide + eribulin 
treatment arm and on Study Day 2 for patients on the eribulin monotherapy treatment arm), a 
urine pregnancy testing will be performed. Any positive urine HCG results will be further 
confirmed by a serum HCG test. A negative pregnancy result is required before the patient 
may receive study medication. Pregnancy tests will also be done whenever one menstrual 
cycle is missed during the active treatment period or when potential pregnancy is otherwise 
suspected, as determined by the Investigator, and these evaluations will be recorded in the 
patient's source data and eCRF. In the case of a positive HCG test, the patient will be 
withdrawn from study drugs, but may remain in the study for survival follow-up. A urine 
pregnancy test will also be conducted at the EoT visit. Pregnancy tests may also be repeated 
as per request of IRB/IECs or if required by local regulations. 
6. 
STUDY MEDICATION 
The investigational medicinal product (IMP; as defined by EU regulation) in this study is 
balixafortide. The other drug to be used in this study is eribulin. 
6.1 
Study Drug Administration 
6.1.1 
Dosing and Administration 
Patients will be randomized to one of the following two treatment regimens: 
 
Balixafortide + eribulin treatment arm 
Balixafortide will be administered on Days 1−3 and Days 8−10 and eribulin will be 
administered on Days 2 and 9 of each 21-day cycle. 
Cycle Scheme: 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
POL6326 
1 
2 
3 
treatment break 
8 
9 
10 
treatment break 
Eribulin 
 
2 
treatment break 
9 
treatment break 
 
Eribulin monotherapy treatment arm 
Eribulin will be administered on Days 2 and 9 of each 21-day cycle. 
Cycle Scheme: 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Eribulin 
 
2 
treatment break 
9 
treatment break 
 
Balixafortide will be administered, at a dose of 5.5 mg/kg, IV over a minimum of 2 hours 
±10 minutes; however, the infusion time of balixafortide can be increased to a maximum of 
3 hours at the discretion of the treating physician, for reasons of patient tolerability (i.e. to 
manage IRRs).   
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Eribulin should be administered IV at a dose of 1.4 mg/m2 over 2 to 5 minutes on Days 2 and 
9 of each 21-day cycle; note: this dose is expressed as the salt, eribulin mesylate; however, 
in some countries this dose is expressed as the base, equivalent to eribulin 1.23 mg/m2. In the 
balixafortide + eribulin treatment arm, eribulin will be administered within 45 minutes after the 
end of the balixafortide infusion. The eribulin dose should be modified in patients with hepatic 
and/or renal impairment as described in the regulatory label for eribulin in the country where 
the patient is being treated or as described in Table 4 (Section 6.1.2) for other countries. 
Crossover will not be allowed at any time after randomization. 
6.1.2 
Dose Modifications (including delays and interruptions) 
Balixafortide 
Balixafortide dosing may be modified for reasons of patient tolerability as described below. 
Patients are to be instructed to notify Investigators at the first occurrence of any adverse sign 
or symptom. 
Dosing modifications for balixafortide may occur in 2 ways: 
• 
Within a cycle: dosing interruption during a given treatment cycle until there is 
adequate recovery to Grade 1 or lower. 
• 
Between cycles: administration of the next cycle may be delayed due to persistent 
toxicity.  
 
Based on currently available data, there are no dose reductions recommended for 
balixafortide. Investigators should discuss with the Sponsor in a timely manner, any 
balixafortide dose reduction they feel warranted for that patient due to AEs and possible 
resumption of balixafortide at the full dose. 
In the rare event that patients are discontinued from balixafortide treatment due to treatment-
related toxicity, patients should attend the EoT Visit, the 30-day Safety Follow-up visit, and the 
Long-term Follow-up visits.   
 
Eribulin 
The recommended dose reductions for eribulin are presented in Table 4 and based on the US 
label (43) as reference. In countries where eribulin is approved, guidance on dose modification 
provided in the local, currently approved eribulin label may be followed. The eribulin dose 
should not be escalated after it has been reduced. 
 
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Table 4 
Recommended dose reductions for eribulin 
Event description 
Recommended dose 
 
Expressed as salt 
(eribulin mesylate) 
Expressed as base 
(eribulin) 
Mild hepatic impairment (Child-Pugh A) 
1.1 mg/m2 
0.97 mg/m2 
Moderate hepatic impairment (Child Pugh B) 
0.7 mg/m2 
0.62 mg/m2 
Moderate 
or 
severe 
renal 
impairment 
(CrCl 
15−49 mL/min) 
1.1 mg/m2 
0.97 mg/m2 
Permanently reduce the 1.4 mg/m2 of eribulin mesylate 
dose (equivalent to 1.23 mg/m2 eribulin base) for any of 
the following  
 
 
ANC <500/mm3 for >7 days  
1.1 mg/m2 
0.97 mg/m2 
ANC <1,000/mm3 with fever or infection  
1.1 mg/m2 
0.97 mg/m2 
Platelets <25,000/mm3 
1.1 mg/m2 
0.97 mg/m2 
Platelets <50,000/mm3 requiring transfusion  
1.1 mg/m2 
0.97 mg/m2 
Non-hematological Grade 3 or 4 toxicities  
1.1 mg/m2 
0.97 mg/m2 
Omission or delay of Day 9 eribulin dose in previous cycle 
for toxicity  
1.1 mg/m2 
0.97 mg/m2 
Occurrence of any event requiring permanent dose 
reduction while receiving 1.1 mg/m2  
0.7 mg/m2 
0.62 mg/m2 
Occurrence of any event requiring permanent dose 
reduction while receiving 0.7 mg/m2  
Discontinue eribulin 
Discontinue eribulin 
ANC: absolute neutrophil count; CrCl: creatinine clearance.   
Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0.  
Source: Eisai Inc. (2017). Full prescription information for HALAVEN® US (43). 
 
6.1.2.1 Dosing Delays or Interruptions 
Patients will start study medication within 3 days from randomization as outlined in the Study 
Schedule (Section 1.1). Subsequent cycles of treatment should be started within 3 days of 
completing the previous cycle. Any delays beyond this that are being considered to the 
beginning of a cycle for logistical or scheduling reasons should be discussed with the Sponsor 
on a case by case basis. 
If study medication during a cycle is delayed for <14 days (counted from the beginning of 
dosing in that cycle), then treatment can be resumed during that cycle. In these circumstances, 
the total duration of a cycle could potentially be extended up to 27 days. 
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If study medication during a cycle is delayed for ≥14 days (counted from the beginning of 
dosing in that cycle), then treatment for that cycle cannot be resumed. Instead, the next cycle 
will be initiated as planned. If the next cycle cannot be initiated as planned, the patient should 
be discontinued from treatment unless discussed and agreed otherwise with the Sponsor.   
The doses of balixafortide on Days 1, 2 and 3 are interdependent with the eribulin dose on 
Day 2. Similarly, the doses of balixafortide on Days 8, 9 and 10 are interdependent with the 
eribulin dose on Day 9. Therefore, if an eribulin dose is delayed by a few days during a cycle, 
then the adjunctive balixafortide doses must also be delayed accordingly during that cycle. 
Although delays of <14 days (counted from the beginning of dosing in that cycle) may change 
the days on which doses are given in relation to the Schedule, the interval between doses in 
a cycle should remain the same as those shown in Section 6.1.1. If a dose of eribulin is 
omitted, the corresponding dose/s of balixafortide must also be omitted. Some examples of 
the circumstances that could arise are given below: 
• 
Example 1, if eribulin is given on Day 3 instead of Day 2, then balixafortide can be 
given on Days 2, 3 and 4 instead of on Days 1, 2 and 3.  
• 
Example 2, if eribulin is given on Day 12 instead of Day 9, then balixafortide can be 
given on Days 11, 12 and 13. 
• 
Example 3, if eribulin is omitted on Day 9, then the balixafortide on Days 8, 9, and 10 
can also be omitted. 
 
Tumor assessments must continue to be performed according to the Study Schedule 
regardless of any dosing delay (Section 8.2).   
 
Recommended Dose Delays for Eribulin 
Do not administer eribulin on Day 2 or Day 9, if any of the following occur: 
• 
ANC <1000/mm3. 
• 
Platelets <75000/mm3. 
• 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 non-
hematological toxicities. 
 
The Day 9 eribulin dose may be delayed for a maximum of 1 week. If toxicities:  
• 
Do not resolve or improve to CTCAE Grade ≤ 2 severity by Day 16, omit the dose. 
• 
Resolve or improve to CTCAE Grade ≤ 2 severity by Day 16, administer the eribulin at 
a reduced dose (Table 4) and initiate the next cycle no sooner than 2 weeks later. 
 
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the Investigator. This study requires adherence to the ASCO guidelines for 
minimizing the incidence of febrile neutropenia, including the recommended prophylactic use 
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of CSFs, where appropriate at the discretion of the Investigator (Appendix 7 ASCO Guidance 
on the Use of CSFs) (54).   
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Accountability 
The Investigator, or an approved designee, must maintain records of the product’s delivery to 
the study site, the inventory at the site, the use for each patient, and will ensure that all study 
drugs are stored in a secure, limited access area. These records must include dates, 
quantities, batch/serial numbers, expiry dates (if applicable), and the unique code numbers 
assigned to the study drug(s) and study patients. A temperature log of the medication storage 
refrigerator must also be kept. Investigators must maintain records that document adequately 
that the patients were provided with the doses specified by the Protocol and reconcile all study 
drug(s) received from the Sponsor.  
To ensure adequate records, all study medications will be accounted for on an on-going basis 
throughout the study in drug accountability forms at the study site. Records will be kept in 
accordance with the applicable regulatory requirements and the Investigator will ensure that 
study medication is dispensed only by qualified site staff. These records will be independently 
monitored by a Study monitor. 
6.2.2 
Formulation, Appearance, Packaging, and Labelling 
Balixafortide is provided in 15R (15 mL) single-use glass vials (European Pharmacopoeia [Ph. 
Eur.] hydrolytic class I) with serum stoppers, aluminum seal and plastic flip-off caps as a clear, 
colorless, aqueous concentrate for solution for infusion in phosphate buffered, isotonic sodium 
chloride. Each vial contains 11 mL extractable volume (385 mg/vial) of balixafortide. Vials are 
provided at 2-8°C in boxes (as secondary package). Vials are individually labelled and new 
vial(s) will be used for each dose administration. 
Balixafortide is labelled in local language. Labelling is performed according to Annex 13 of the 
Good Manufacturing Practice (GMP) guidelines of the European Commission, ICH GCP 
guidelines, and local laws. 
Eribulin is provided as a clear, colorless aqueous solution for injection, in type I glass vials 
with Teflon-coated, butyl rubber stoppers and flip-off aluminum over seals. Each vial contains 
2 mL of eribulin solution with ethanol anhydrous, water for injections, hydrochloric acid (for 
pH-adjustment) and sodium hydroxide (for pH-adjustment) as excipients. Vials are provided 
at 15-25°C in boxes. Vials are individually labelled and new vial(s) will be used for each dose 
administration. 
6.2.3 
Product Storage and Stability 
Study medication must be stored in securely locked areas not generally accessible until 
administered to the patients. The key to the storage area is to be kept by the Investigator (or 
delegated person responsible for the study drug). The store will be accessible only to those 
persons authorized by the Investigator to dispense/administer study medication under this 
protocol. 
Further details on drug handling will be provided in a separate pharmacy manual. 
Balixafortide and eribulin supplied by the Sponsor, are to be used exclusively in this clinical 
trial according to the instructions of this protocol. 
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Unopened vials of balixafortide can be stored at 2-8°C for at least 2 years when protected 
from light. 
Unopened vials of eribulin can be stored at 15-25°C for 5 years. In countries where eribulin is 
approved, the local label should be consulted for storage instructions.  
6.2.4 
Preparation 
To minimize the risk of microbial contamination, balixafortide and eribulin should be used 
immediately after opening. If this is not feasible, the in-use storage times apply as specified 
below. Please refer to the pharmacy manual for additional information. 
Balixafortide 
The dose will be adjusted per mg/kg body weight. The concentrate for solution for infusion will 
be diluted with isotonic saline (0.9%) solution for infusion (pharmacopeial grade) to obtain a 
final infusion solution with a concentration of 0.5 mg/mL balixafortide.  
The in-use storage time of the final solution for infusion should not exceed 24 hours at 2-8°C 
or 6 hours at room temperature. 
Eribulin 
The Investigator (or designee) will aseptically withdraw the required amount of eribulin from 
the single-use vial and administer either undiluted or after dilution in up to 100 mL with isotonic 
saline (0.9%) solution.   
Undiluted eribulin can be stored in the syringe for up to 4 hours at room temperature or for up 
to 24 hours under refrigeration (2-8°C). Diluted solutions of eribulin can be stored for up to 
4 hours at room temperature or up to 24 hours under refrigeration. 
Eribulin must not be mixed with other medicinal products and should not be diluted in glucose 
5% infusion solution. Eribulin should only be prepared and administered by personnel 
appropriately trained in handling of cytotoxic agents. Pregnant staff should not handle eribulin. 
6.3 
Assessment of Compliance 
Study drugs must be used only as directed in the Protocol. As the study drugs will be 
administered at the study site by the Investigator or trained study site staff, it is not considered 
necessary to assess subject compliance in this study. 
7. 
STUDY ASSESSMENTS AND PROCEDURES 
All assessments should be performed prior to dosing with study medications on the visit day 
unless otherwise indicated. Acceptable visit time windows are presented in the Study 
Schedules (Section 1.1). For the purposes of this study, one cycle is 21 days. For dose 
interruptions, see Section 6.1.2.1. 
Every effort should be made to ensure that the protocol-required activities and procedures are 
completed as described. However, there may be circumstances, outside of the control of the 
Investigator, which may make it unfeasible to perform the activity. In these cases, the 
Investigator will take all steps necessary to ensure the safety and well-being of the patient. 
When a protocol-required activity cannot be performed, the Investigator will document the 
reason for this and any corrective and preventive actions which he/she has taken to ensure 
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that normal processes are adhered to as soon as possible. The Sponsor will be informed of 
these incidents in a timely fashion.  
7.1 
Screening Visit (Day –21 to –1) 
On the day of the Screening, the Investigator or designee must obtain the patient's consent 
before performing any protocol-related procedure and assessment (see Section 15.2 for 
further details).   
Once the consent is obtained, the following procedures and assessments will be performed 
and recorded in the patient's source data and CRF: 
All patients: 
• 
Informed consent. 
• 
Interactive Web Response System (IWRS)/IRT registration─the patient number will be 
allocated. 
• 
Patient eligibility (inclusion/exclusion criteria). 
• 
Demographics (gender, date of birth, race and ethnicity) and baseline data. 
• 
Medical history (e.g. important medical, surgical, and allergic conditions from the patient's 
medical history that could have an impact on the patient's evaluation, all cancer history, all 
previous cancer therapy, and all relevant, current medical conditions that are present at 
the time of signing informed consent).  Any pre-planned intervention or procedure to occur 
during the study will also be recorded. 
• 
Stratification factors for the trial i.e. whether HR status positive or negative (based on ER 
or PgR status), previous lines of chemotherapy received for locally recurrent or metastatic 
BC, whether CDK 4/6 inhibitor treatment was received previously, whether visceral or non-
visceral disease is present. Visceral metastases will include brain, pulmonary, pleural, 
hepatic and peritoneal involvement (including pleural effusions and ascites). Any other 
sites of metastases (e.g. bone, lymph nodes, and skin) will be considered to be non-
visceral. Patients with visceral metastases, irrespective of the presence of any other 
metastatic sites (e.g. bone), will be categorized as visceral. All other patients without 
visceral metastases will be categorized as non-visceral. 
• 
Prior/concomitant therapy/medications taken up to 28 days before the start of study 
medication (see Section 5.4.1). 
• 
Patient reported health outcome QoL questionnaires (see Section 11.3). 
• 
Standard, complete physical examination (see Section 9.6). 
• 
Vital signs (resting BP, respiratory rate, pulse rate, and body temperature; see 
Section 9.7). 
• 
Weight and height. 
• 
ECOG performance status (see Section 9.6). 
• 
SAEs will be recorded from the time that the ICF is signed (see Section 9.2). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9). 
Screening blood tests should be taken within 7 days prior to randomization. 
• 
Serum pregnancy test (β-HCG) for women of child bearing potential (see Section 5.4.5) 
only, no more than 7 days prior to Randomization.  
• 
Females of child bearing potential must be instructed to use adequate, highly effective 
contraception whilst they or their male partners are on this study from randomization until 
3 months after the last dose of study medication (Section 5.4.5). Male patients must 
commit to using an approved form of birth control, including double-barrier method of 
contraception (e.g. consistent and correct use of male condom with diaphragm or male 
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condom with cervical cap) or sterilization method from randomization until 3 months after 
the last dose of study medication (Section 5.4.5). Male patients are also encouraged to 
seek advice on conservation of sperm prior to beginning study medication because of the 
possibility of irreversible infertility due to therapy with eribulin.    
• 
Date and results of last CT/MRI scan. If no scan has been performed in the 30 days prior 
to Randomization a scan should be performed (see Section 8.2.1). 
• 
Date and results of last bone scan. If no scan has been performed in the 30 days prior to 
Randomization a scan should be performed (see Section 8.2.1). 
• 
12-lead ECG (see Section 9.8). 
• 
Date and results of last tumor biopsy (see Section 11.2.1).  
• 
For patients who have had a previous tumor biopsy at any time, consent will be required 
to donate this tissue for biomarker assessment. If multiple biopsies are available, it is 
recommended to collect a sample of each. If such tumor tissue is not available, then the 
patient will be requested to provide a fresh tumor biopsy (see Section 11.2.1). If a fresh 
tumor biopsy is not available, the patient's refusal to provide a tumor biopsy or the lack of 
lesions from which a biopsy can be collected will be documented in the patient's source 
data and eCRF. 
 
Patients at Selected Sites Only 
For patients at selected sites, the following additional assessments will be performed: 
• 
Patients can optionally consent to fresh tumor biopsy at Screening and subsequent 
timepoints as defined in the Study Schedules (Section 1.1) for exploratory biomarkers. If 
a biopsy has already been performed within 30 days prior to randomization and tumor 
tissue is still available, then the fresh tumor biopsy is not required during Screening (see 
Section 11.2.1).  
7.2 
Randomization 
The Investigator will review the patient’s laboratory test results and confirm that the patient is 
eligible for the study. If the patient is eligible, the Investigator will randomize the patient to the 
study via the IRT. The IRT will allocate the patient to the respective treatment arm. Further 
details are provided in the IRT manual. 
No patient should be randomized into the study more than once. If a patient is randomized in 
error (e.g. randomization number is allocated incorrectly) and/or receives the wrong treatment, 
the Sponsor should be notified as soon as the error is discovered (Section 9.4).  
7.3 
Treatment Period─Balixafortide + Eribulin Treatment Arm Only 
7.3.1 
Cycle 1 
7.3.1.1 Cycle 1 Day 1 
Patients will start study medication within 3 days from randomization as outlined in the Study 
Schedule (Section 1.1). 
The following procedures and assessments will be performed following randomization: 
Before Balixafortide Administration: 
• 
Patient reported health outcome QoL questionnaires (see Section 11.3). 
• 
Targeted physical examination (see Section 9.6). 
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• 
Vital signs (resting BP, respiratory rate, pulse rate, and body temperature; see 
Section 9.7). 
• 
Weight  
• 
ECOG performance status (see Section 9.6). 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the Screening Visit (see Section 5.4.1). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9); blood 
test results must be available within 24 hours prior to study drug administration.  
• 
Urine pregnancy test for women of child bearing potential (see Section 5.4.5.1). 
• 
12-lead ECGs, 2 baseline ECG recordings taken within 1 hour prior to administration of 
balixafortide (see Section 9.8). 
• 
Blood samples for immunogenicity taken immediately before starting balixafortide infusion 
(see Section 11.1). 
• 
Blood samples for exploratory biomarkers in all patients taken immediately before starting 
balixafortide infusion (see Section 11.2.2). 
• 
IWRS/IRT registration. 
 
Balixafortide Administration (see Section 6.1).  
 
Immediately After Completing Balixafortide Infusion: 
• 
Blood samples for exploratory biomarkers in all patients (see Section 11.2.2). 
 
Patients at Selected Sites Only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
Blood samples for other exploratory biomarkers in patients at selected sites (see 
Section 11.2.2). 
7.3.1.2 Cycle 1 Day 2 
Before Balixafortide Administration: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
IWRS/IRT registration. 
• 
12-lead ECG before starting balixafortide infusion (see Section 9.8). 
• 
Blood sample for PK taken immediately before starting balixafortide infusion, see 
Section 10.1. 
 
Balixafortide Administration (see Section 6.1). 
 
After Balixafortide Administration, but Before Administration of Eribulin: 
• 
Blood samples for exploratory biomarkers in all patients taken immediately after 
completing balixafortide infusion, but before administration of eribulin (see Section 11.2.2). 
• 
Blood sample for PK taken immediately after completing balixafortide infusion, see 
Section 10.1. 
 
Eribulin Administration (see Section 6.1). 
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After Study Medication Administration: 
• 
12-lead ECG within 1 hour after completing eribulin infusion (see Section 9.8). 
• 
One additional blood sample scheduled flexibly with precise recording, at 1−20 hours after 
completing the infusion of balixafortide on Day 2, see Section 10.1.  
 
Patients at Selected Sites Only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
Blood sample for other exploratory biomarkers in patients at selected sites (see 
Section 11.2.2).  
7.3.1.3 Cycle 1 Day 3 
Before Balixafortide Administration: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
IWRS/IRT registration. 
 
Balixafortide Administration (see Section 6.1). 
 
Immediately After Completing Balixafortide Administration: 
• 
Blood samples for exploratory biomarkers in all patients taken immediately after 
completing balixafortide infusion (see Section 11.2.2). 
 
7.3.1.4 Cycle 1 Day 8 
Before Balixafortide Administration: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9); blood 
test results must be available within 24 hours prior to study drug administration.   
• 
IWRS/IRT registration. 
• 
Blood samples for immunogenicity taken immediately before starting balixafortide infusion 
(see Section 11.1). 
• 
Blood samples for exploratory biomarkers in all patients taken immediately before starting 
balixafortide infusion (see Section 11.2.2). 
 
Balixafortide Administration (see Section 6.1). 
 
Immediately After Completing Balixafortide Infusion: 
• 
Blood sample for PK, see Section 10.1. 
 
Patients at Selected Sites Only: 
For patients at selected sites, the following additional assessments will be performed: 
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• 
Blood samples for other exploratory biomarkers in patients at selected sites (see 
Section 11.2.2). 
7.3.1.5 Cycle 1 Day 9 
Before Balixafortide Administration: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
12-lead ECG before starting balixafortide infusion (see Section 9.8). 
• 
IWRS/IRT registration. 
• 
Blood sample for PK taken immediately before starting balixafortide infusion, see 
Section 10.1.  
• 
Blood samples for exploratory biomarkers in all patients taken immediately before starting 
balixafortide infusion (see Section 11.2.2). 
 
Balixafortide Administration (see Section 6.1). 
 
Eribulin Administration (see Section 6.1). 
 
After Eribulin Administration: 
• 
12-lead ECG within 1 hour after completing eribulin infusion (see Section 9.8). 
7.3.1.6 Cycle 1 Day 10 
Before Balixafortide Administration: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
IWRS/IRT registration.  
 
Balixafortide Administration (see Section 6.1). 
7.3.2 
Subsequent Cycles  
7.3.2.1 Day 1 
Before Balixafortide Administration: 
• 
Patient reported health outcome QoL questionnaire (see Section 11.3). 
• 
Targeted physical examination (see Section 9.6). 
• 
Vital signs (resting BP, respiratory rate, pulse rate, and body temperature; see 
Section 9.7). 
• 
Weight. 
• 
ECOG performance status (see Section 9.6). 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9; blood test 
results must be available within 24 hours prior to study drug administration). 
• 
Urine pregnancy test for women of child bearing potential (see Section 5.4.5.1). 
• 
IWRS/IRT registration. 
 
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Cycles 2, 3, 5, 7 and then every alternate cycle only: 
• 
Blood samples for immunogenicity taken immediately before starting balixafortide infusion 
(see Section 11.1). 
Cycles 3 only: 
• 
Blood samples for exploratory biomarkers in all patients taken immediately before starting 
balixafortide infusion (see Section 11.2.2). 
 
Balixafortide Administration (see Section 6.1).  
 
Immediately After Completing Balixafortide Infusion: 
Cycle 3 only: 
• 
Blood samples for exploratory biomarkers in all patients (see Section 11.2.2). 
 
Patients at Selected Sites Only: 
Cycle 3 only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
Blood samples for other exploratory biomarkers in patients at selected sites (see 
Section 11.2.2). 
7.3.2.2 Day 2 
Before Balixafortide Administration: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
12-lead ECG before starting balixafortide infusion (see Section 9.8). After Cycle 2, the 
frequency of ECG recordings can be reduced to every 2 cycles if deemed clinically 
appropriate (i.e. absence of ECG findings in earlier assessments). 
• 
IWRS/IRT registration. 
Cycle 3 only: 
• 
Blood sample for PK taken immediately before starting balixafortide infusion (see 
Section 10.1). 
 
Balixafortide Administration (see Section 6.1). 
 
After Balixafortide Administration, but Before Administration of Eribulin: 
Cycle 3 only: 
• 
Blood samples for exploratory biomarkers in all patients taken immediately after 
completing balixafortide infusion, but before administration of eribulin (see Section 11.2.2). 
Cycles 2, 3, 5, and 7 only: 
• 
Blood sample for PK in all patients taken immediately after completing balixafortide 
infusion, see Section 10.1. 
 
Eribulin Administration (see Section 6.1). 
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After Eribulin Administration: 
• 
12-lead ECG within 1 hour after completing eribulin infusion (see Section 9.8). After 
Cycle 2 the frequency of ECG recordings can be reduced to every 2 cycles if deemed 
clinically appropriate (i.e. absence of ECG findings in earlier assessments). 
 
Patients at Selected Sites Only: 
Cycle 3 only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
Blood samples for other exploratory biomarkers in patients at selected sites (see 
Section 11.2.2). 
7.3.2.3 Day 3 
Before Balixafortide Administration: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
IWRS/IRT registration. 
Cycle 5 and 7 only: 
• 
Blood sample for PK taken immediately before starting balixafortide infusion, see 
Section 10.1. 
 
Balixafortide Administration (see Section 6.1). 
 
Immediately After Completing Balixafortide Administration: 
Cycle 3 only: 
• 
Blood samples for exploratory biomarkers in all patients taken immediately after 
completing balixafortide infusion (see Section 11.2.2). 
 
7.3.2.4 Day 4 (Cycle 3 only) 
Patients at Selected Sites Only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
Blood sample for PK at 24 hours (±4 hours) after completing the balixafortide infusion on 
Day 3 (see Section 10.1). 
• 
Blood samples for exploratory biomarkers taken 24 hours (±4 hours) after completing the 
balixafortide infusion on Day 3, only in those patients scheduled to have blood samples 
for PK on Cycle 3, Day 4 (see Section 11.2.2). 
7.3.2.5 Day 5 (Cycle 3 only) 
Patients at Selected Sites Only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
Blood sample for PK at 44 hours (±4 hours) after completing the balixafortide infusion on 
Day 3 (see Section 10.1). 
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• 
Blood samples for exploratory biomarkers taken 44 hours (±4 hours) after completing the 
balixafortide infusion on Day 3, only in those patients scheduled to have blood samples 
for PK on Cycle 3, Day 5 (see Section 11.2.2). 
7.3.2.6 Day 8 
Before Balixafortide Administration:  
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9) blood test 
results must be available within 24 hours prior to study drug administration.   
• 
IWRS/IRT registration. 
Cycle 2 only: 
• 
Blood sample for immunogenicity taken immediately before starting balixafortide infusion 
(see Section 11.1). 
Cycle 3 only: 
• 
Blood samples for exploratory biomarkers in all patients taken immediately before starting 
balixafortide infusion (see Section 11.2.2). 
 
Balixafortide Administration (see Section 6.1). 
 
Immediately After Completing Balixafortide Infusion: 
Cycle 2 only: 
• 
Blood sample for PK, see Section 10.1. 
7.3.2.7 Day 9 
Before Balixafortide Administration: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
12 lead ECGs before starting balixafortide infusion (see Section 9.8). After Cycle 2, the 
frequency of ECG recordings can be reduced to every 2 cycles if deemed clinically 
appropriate (i.e. absence of ECG findings in earlier assessments).  
• 
IWRS/IRT registration. 
Cycle 2 only: 
• 
Blood sample for PK taken immediately before starting balixafortide infusion (see 
Section 10.1). 
Cycles 3 only: 
• 
Blood samples for exploratory biomarkers taken immediately before starting balixafortide 
infusion (see Section 11.2.2). 
 
Balixafortide Administration (see Section 6.1). 
 
Eribulin Administration (see Section 6.1). 
 
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After Eribulin Administration: 
• 
12-lead ECG within 1 hour after completing eribulin infusion (see Section 9.8). After 
Cycle 2, the frequency of ECG recordings can be reduced to every 2 cycles if deemed 
clinically appropriate (i.e. absence of ECG findings in earlier assessments). 
 
Patients at Selected Sites Only: 
Cycle 2 only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
Optional tumor biopsy (see Section 11.2.1); alternatively, biopsy can be performed on 
Day 10 if preferred. 
• 
Blood samples for other exploratory biomarkers in patients at selected sites who are 
scheduled to have an optional, fresh tumor biopsy (see Section 11.2.2); the blood sample 
can be taken before or after the biopsy. 
7.3.2.8 Day 10 
Before Balixafortide Administration: 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
IWRS/IRT registration. 
 
Balixafortide Administration (see Section 6.1). 
7.3.2.9 Day 21 
All patients (from the date of randomization every 6 weeks [±7 days] during the first 
year, and then every 12 weeks [±7 days] thereafter until PD is documented): 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
CT/MRI scan (see Section 8.2.2). Scans performed to assess progression or response 
must match the baseline scan (i.e. if CT scan at baseline then CT scan for all other scans).  
7.4 
Treatment Period─Eribulin Monotherapy Treatment Arm Only 
7.4.1 
Cycle 1 
Patients will start study medication within 3 days from randomization as outlined in the Study 
Schedule (Section 1.1). 
The following procedures and assessments will be performed following randomization. 
7.4.1.1 Cycle 1 Day 2 
Before Eribulin Administration: 
• 
Patient reported health outcome QoL questionnaires (see Section 11.3). 
• 
Targeted physical examination (see Section 9.6). 
• 
Vital signs (resting BP, respiratory rate, pulse rate, and body temperature; see 
Section 9.7). 
• 
Weight. 
• 
ECOG performance status (see Section 9.6). 
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• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9); blood 
test results must be available within 24 hours prior to study drug administration.  
• 
Urine pregnancy test for women of child bearing potential (see Section 5.4.5.1). 
• 
12-lead ECG before starting eribulin infusion (see Section 9.8). 
• 
IWRS/IRT registration. 
• 
Blood samples for exploratory biomarkers in all patients taken immediately before starting 
eribulin infusion (see Section 11.2.2). 
 
Eribulin Administration (see Section 6.1). 
 
After Eribulin Administration: 
• 
12-lead ECG within 1 hour after completing eribulin infusion (see Section 9.8). 
 
Patients at Selected Sites Only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
Blood sample for other exploratory biomarkers in patients at selected sites (see 
Section 11.2.2).  
7.4.1.2 Cycle 1 Day 9 
Before Eribulin Administration:  
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9); blood 
test results must be available within 24 hours prior to study drug administration.  
• 
12-lead ECGs before starting eribulin infusion (see Section 9.8). 
• 
IWRS/IRT registration. 
• 
Blood samples for exploratory biomarkers in all patients taken immediately before starting 
eribulin infusion (see Section 11.2.2). 
 
Eribulin Administration (see Section 6.1). 
 
After Eribulin Administration: 
• 
12-lead ECG within 1 hour after completing eribulin infusion (see Section 9.8). 
7.4.2 
Subsequent Cycles 
7.4.2.1 Day 2 
Before Eribulin Administration:  
• 
Patient reported health outcome QoL questionnaires (see Section 11.3). 
• 
Targeted physical examination (see Section 9.6). 
• 
Vital signs (resting BP, respiratory rate, pulse rate, and body temperature; see 
Section 9.7).  
• 
Weight. 
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• 
ECOG performance status (see Section 9.6). 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9); blood 
test results must be available within 24 hours prior to study drug administration). 
• 
Urine pregnancy test for women of child bearing potential (see Section 5.4.5.1). 
• 
12-lead ECG before starting eribulin infusion (see Section 9.8). After Cycle 2, the 
frequency of ECG recordings can be reduced to every 2 cycles if deemed clinically 
appropriate (i.e. absence of ECG findings in earlier assessments). 
• 
IWRS/IRT registration. 
Cycle 3 only: 
• 
Blood samples for exploratory biomarkers in all patients to be taken immediately before 
starting the eribulin infusion (see Section 11.2.2). 
 
Eribulin Administration (see Section 6.1). 
 
After Eribulin Administration: 
• 
12-lead ECG within 1 hour after completing eribulin infusion (see Section 9.8). After 
Cycle 2, the frequency of ECG recordings can be reduced to every 2 cycles if deemed 
clinically appropriate (i.e. absence of ECG findings in earlier assessments). 
 
Patients at Selected Sites Only: 
Cycle 3 only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
Blood samples for other exploratory biomarkers in patients at selected sites (see 
Section 11.2.2). 
7.4.2.2 Day 9 
Before Eribulin Administration:  
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9); blood 
test results must be available within 24 hours prior to study drug administration.  
• 
12-lead ECG before starting eribulin infusion (see Section 9.8). After Cycle 2, the 
frequency of ECG recordings can be reduced to every 2 cycles if deemed clinically 
appropriate (i.e. absence of ECG findings in earlier assessments). 
• 
IWRS/IRT registration. 
Cycle 3 only: 
• 
Blood samples for exploratory biomarkers in all patients to be taken immediately before 
starting eribulin infusion (see Section 11.2.2). 
 
Eribulin Administration (see Section 6.1). 
 
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After Eribulin Administration: 
• 
12-lead ECG within 1 hour after completing eribulin infusion (see Section 9.8). After 
Cycle 2, the frequency of ECG recordings can be reduced to every 2 cycles if deemed 
clinically appropriate (i.e. absence of ECG findings in earlier assessments). 
 
Patients at Selected Sites Only: 
Cycle 2 only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
Optional tumor biopsy (see Section 11.2.1). 
• 
Blood samples for other exploratory biomarkers in patients at selected sites who are 
scheduled to have an optional, fresh tumor biopsy (see Section 11.2.2); the blood sample 
can be taken before or after the biopsy. 
7.4.2.3 Day 21 
All patients (from the date of randomization every 6 weeks [±7 days] during the first 
year, and then every 12 weeks [±7 days] thereafter until PD is documented): 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1) 
• 
CT/MRI scan (see Section 8.2.2). Scans performed to assess progression or response 
must match the baseline scan (i.e. if CT scan at baseline then CT scan for all other scans).  
7.5 
Unscheduled Visit 
Additional assessments to those scheduled for this study should be performed as indicated at 
the Investigator's discretion (e.g. due to concerns about patient safety, patient's clinical status, 
or if additional radiographic tumor assessments are required because there is clinical 
suspicion of disease progression); the findings of an unscheduled examination should be 
recorded in the patient's source data and eCRF.  
7.6 
End of Treatment Visit 
Patients who discontinue treatment will attend the EoT Visit (i.e. withdrawal) as soon as 
possible, within 7 days after discontinuation and prior to initiation of any new anti-cancer 
therapy, regardless of the reason for discontinuation.   
All patients: 
• 
Patient reported health outcome QoL questionnaires (see Section 11.3). 
• 
Targeted physical examination (see Section 9.6). 
• 
Vital signs (resting BP, respiratory rate, pulse rate, and body temperature; see 
Section 9.7). 
• 
Weight. 
• 
ECOG performance status (see Section 9.6). 
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit (see Section 5.4.1). 
• 
12-lead ECG (see Section 9.8). 
• 
Clinical laboratory tests (hematology, chemistry, and urinalysis; see Section 9.9). 
• 
Urine pregnancy test for women of child bearing potential (see Section 5.4.5.1). 
• 
CT/MRI scan (see Section 8.2.2) in patients who are discontinued from study medication 
in the absence of PD; however, patients who have already demonstrated objective PD 
(according to RECIST v 1.1) do not need to have scans repeated at the EoT visit.   
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• 
Blood samples for immunogenicity only for patients from the balixafortide + eribulin 
treatment arm (see Section 11.1). 
• 
Document reason for treatment discontinuation. 
• 
IWRS/IRT registration. 
 
Patients at Selected Sites Only: 
For patients at selected sites, the following additional assessments will be performed: 
• 
Optional tumor biopsy (see Section 11.2.1). 
• 
Blood samples for other exploratory biomarkers in patients at selected sites (see 
Section 11.2.2). 
 
7.7 
30-Day Safety Follow-up 
The 30-day safety follow-up visit will be scheduled 30 days (and no later than 37 days) after 
the last dose of study drug and can be conducted over the telephone. If for any reason the 
safety follow-up occurs earlier than scheduled (e.g. initiation of new anticancer therapy, 
withdrawal of consent), the time of the visit should be documented along with the reasons for 
the early follow-up; the data from these visits will be evaluated separately. 
All Patients:  
• 
AE reporting (see Section 9.2). 
• 
Concomitant therapy/medications taken since the previous visit to be recorded for patients 
with unresolved AEs (see Section 5.4.1). 
 
7.8 
Long-term Follow-up  
Every effort should be made to collect and record all anti-cancer medicines that the patient 
receives during Long-term Follow-up in the patient's source data and eCRF until the end of 
study. 
7.8.1 
PD Follow-up 
Regardless of treatment arm, patients who are discontinued from study medication for any 
reason, in the absence of PD, will undergo repeat imaging and tumor response assessments 
(including CT/MRI scans, see Section 8.2.2) every 8 weeks ±7 days (every 12 weeks ±7 days 
if the patient has been on the study for ≥1 year) until PD is documented as per RECIST v1.1, 
or death occurs, or patient is lost to follow-up, or the patient withdraws consent (whichever 
occurs first). If a patient stops study medication and begins other anti-cancer therapy before 
PD is documented, every effort should be made to perform tumor evaluation in these patients 
until disease progression. CT/MRI scan (see Section 8.2.2) performed to assess progression 
must match the baseline scan (i.e. if CT scan at baseline then CT scan for all other scans).  
7.8.2 
Survival Follow-up 
The Investigator will monitor the patient for OS status every 6 months (or more frequently) 
until death, until the patient withdraws consent to follow-up for survival, or until the patient is 
lost to follow-up (whichever occurs first). Survival follow-up can be conducted by telephone. 
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7.9 
Duration of Study Participation 
Patients will attend the study site for the Screening Visits between Day -21 to -1 and then as 
outlined in the Study Schedule Section 1.1. 
Patients will initiate treatment and will continue, as assigned at randomization, until PD by 
RECIST v1.1 criteria is met or until one of the treatment discontinuation or study withdrawal 
criteria, outlined in Section 5.3 is met. 
Patients who discontinue randomized treatment for any of these reasons will be required to 
attend an EoT Visit (Section 7.4) and a 30-Day Safety Follow-up (Section 7.7). Patients who 
have not withdrawn from the study will be entered into the Long-term Follow-up phase 
(Section 7.8) for the determination of PFS and OS, until the first occurrence of any of the 
below: 
• 
Death. 
• 
Loss to follow-up. 
• 
Withdrawal of consent.  
To generate the required number of PFS events for the main analysis, a 12-month recruitment 
period is anticipated with an expected follow-up period of 12-months after the last patient is 
randomized. Patients are expected to be followed for one additional year for OS. The study is 
planned to begin during the first quarter of 2019. 
7.10 
End of Study Definition 
The end of the active treatment phase of the study is defined as the date the last patient 
completes the safety follow-up period (i.e. 30 days [±7 days] after the last study drug 
administration). 
The end of the study (study completion) is defined as the date on which all patients have 
completed the 30-day Safety Follow-up and when the final OS analysis is completed, this is 
expected to be 2 years after the last patient is enrolled on study.  
In the opinion of the Investigator, those patients who continue to derive benefit from study 
medication, at the end of the study, will be able to continue receiving study medication on an 
individual basis (e.g. separate protocol, or Polyphor providing study medication to the 
Investigator as per local regulations). 
8. 
ASSESSMENT OF EFFICACY 
The Study Schedule of Assessments and sampling are outlined in Section 1.1.  
Tumor response will be assessed locally and centrally. 
8.1 
Independent Review of Disease Response 
A blinded IRC will perform a retrospective review of radiographic images and clinical 
information collected on-study to verify the protocol defined endpoints of disease response 
and progression as assessed by the Investigator. 
It is important that all specified imaging studies and clinical information (including photographs) 
are forwarded to the IRC as each patient enrolls and progresses through the study. 
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Information on materials to be forwarded to the IRC, correct procedures for the coding/blinding 
of the patient’s name/identity, and the return of the source data/documents to the site is 
provided in the imaging plan. 
8.2 
Tumor Assessments 
The Study Schedule of Assessments and sampling are outlined in Section 1.1. Since the 
primary endpoint of the study is PFS, it is critical that tumor assessments are performed 
according to the Study Schedule in a timely and complete manner to allow full comparability 
of the two treatment arms. To prevent the introduction of any bias into the efficacy results, the 
assessment must be performed according to the calendar regardless of any dosing delay or 
interruption. Imaging assessments will be scheduled using the randomization date as the 
reference date for all timepoints and NOT scheduled according to the date of the previous 
imaging timepoint. A delay in the imaging assessment to accommodate a treatment delay is 
not permitted. Incomplete assessment and/or wrong timing (out of Schedule) will result in the 
inability to accurately assess disease status for that timepoint. CT/MRI scan will be used to 
measure target lesions that are selected for response assessment. For a given patient/tumor 
lesion, the same technique for tumor assessment MUST be used throughout the study. 
8.2.1 
Screening or Baseline Tumor Assessment 
The date and results of the patient's last CT/MRI scan and bone scan will be recorded in the 
patient's source data and eCRF. If no CT/MRI scan has been performed in the 30 days prior 
to Randomization a CT/MRI scan must be performed during Screening. Similarly, if no bone 
scan has been performed in the 30 days prior to Randomization a bone scan must be 
performed during Screening. 
CT/MRI scan will be used to measure target lesions that are selected for response 
assessment. For a given patient/tumor lesion, the same technique for tumor assessment 
MUST be used throughout the study. Guidance on measurability of tumors at baseline and 
documentation at baseline is provided in Appendix 3 Summary of RECIST v1.1 Guidelines. 
The following scans must be available for all patients at Screening/Baseline: 
• 
CT/MRI scan of the chest, abdomen, and pelvis. 
• 
CT/MRI scan of any other sites of disease as clinically indicated. 
• 
Clinical assessment of superficial disease which will include photographs of all 
superficial metastatic lesions. All lesion measurements must be recorded in the eCRF. 
• 
Bone scans in order to detect bony sites of disease. Any suspicious abnormalities (i.e. 
hotspots) identified on the bone scans at baseline must be confirmed by X-ray, CT 
scan or MRI scan.   
• 
Baseline brain CT/MRI is only required if signs and symptoms suggest the presence 
of metastatic brain disease or if the patient has a history of stable metastatic brain 
disease (Section 5.1).  
8.2.2 
Post-baseline Tumor Assessments 
Tumor assessments are to be scheduled using the randomization date as the reference date 
for all timepoints; tumor assessments are NOT to be scheduled according to the timepoint of 
the previous tumor assessment.  
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From the date of randomization, patients will be evaluated according to RECIST v1.1 for CR, 
PR, SD, or PD based on CT/MRI scans performed every 6 weeks (±7 days) during the first 
year, and then every 12 weeks (±7 days), thereafter, until PD is documented by RECIST v1.1. 
The RECIST v1.1 definitions of the criteria used to determine tumor response for target lesions 
are provided in Table 5 and for non-target lesions in Table 6. Table 7 provides a summary of 
the overall response calculation that is to be used at each response assessment timepoint 
specified in the Study Schedule for patients who have measurable disease at baseline. When 
patients have non-measurable disease only, Table 8 is to be used. Further information is 
summarized in Appendix 3 Summary of RECIST v1.1 Guidelines. 
 
 
Table 5 
Determination of Objective Tumor Response for Target Lesions 
Tumor Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD)  
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum of diameters of target lesions 
recorded on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered 
progression). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Source: (55) 
Further details can be found in Appendix 3 Summary of RECIST v1.1 Guidelines. 
 
 
 
 
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Table 6 
Determination of Tumor Response for Non-target Lesions 
Tumor Response 
Evaluation of Non-target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis). 
Progressive Disease (PD) 
Unequivocal progression (see Appendix 3 Summary of RECIST v1.1 
Guidelines) of existing non-target lesions. (Note: the appearance of one or 
more new lesions is also considered progression). 
Non-CR/Non-PD  
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Source: (55) 
While some non-target lesions may actually be measurable, they need not be measured and instead should be 
assessed only qualitatively at the timepoints specified in the Study Schedule. Further details can be found in 
Appendix 3 Summary of RECIST v1.1 Guidelines. 
 
 
Table 7 
Determination of Overall Response at each Timepoint specified in the Study 
Schedule for Patients with Measurable Disease at Baseline 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD  
No 
PR 
CR 
Not evaluated  
No 
PR 
PR 
Non-PD 
or 
not 
all 
evaluated 
No 
PR 
SD 
Non-PD 
or 
not 
all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR: complete response; PD: progressive disease; PR: partial response; SD: stable disease. 
Source: (55) 
Further details can be found in Appendix 3 Summary of RECIST v1.1 Guidelines. 
 
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Table 8 
Determination of Overall Response at each Timepoint specified in the Study 
Schedule for Patients with Non-measurable Disease at Baseline 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PDa 
Not all evaluated 
No 
Not evaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR: complete response; PD: progressive disease; SD: stable disease 
Source: (55) 
a. `Non-CR/Non-PD' is preferred over `stable disease' for non-target disease because SD is used as an endpoint 
for assessment of efficacy so to assign this category when no lesions can be measured is not advised. 
Further details can be found in Appendix 3 Summary of RECIST v1.1 Guidelines. 
 
At the discretion of the Investigator, additional radiographic tumor assessments may be done 
at any time if there is clinical suspicion of disease progression; the results of an unscheduled 
scan must be recorded in the patient's source data and eCRF. The methodology used for 
scans to assess progression or response must be the same as those used for the baseline 
scan (i.e. if CT scan at baseline then CT scan for all other scans). 
The local Investigator will assess the presence of disease following CT/MRI scan performed 
at Screening, and those performed subsequently, and record the details in the patient's source 
data and eCRF relative to the previous assessment of disease status/metastatic burden. 
Following initial documentation of an objective response, a confirmatory CT/MRI scan will be 
performed at least 4 weeks later. 
Patients will continue treatment as assigned at randomization until objective PD (according to 
RECIST v1.1) is documented, there is unacceptable toxicity, death occurs, the patient 
withdraws consent, or the patient is lost to follow-up (whichever occurs first). 
CT/MRI will be performed at the EoT visit in patients who are discontinued from study 
medication in the absence of PD; however, patients who have already demonstrated objective 
PD according to RECIST v 1.1 do not need to have scans repeated at the EoT visit. 
Regardless of regimen, patients who are discontinued from study medication for any reason 
in the absence of PD, will also undergo repeat imaging and tumor response assessments 
(including CT/MRI scans) every 8 weeks ±7 days (every 12 weeks [±7 days] if the patient has 
been on the study for ≥1 year), until PD is documented as per RECIST v1.1, or death occurs, 
or patient is lost to follow-up, or the patient withdraws consent (whichever occurs first). If a 
patient stops study medication and begins another anti-cancer therapy before PD is 
documented, every effort should be made to perform tumor evaluation in these patients until 
disease progression. Every effort should be made to collect and record all anti-cancer 
medicines that the patient receives during Long-term Follow-up in the patient's source data 
and eCRF until the end of the study. 
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Patients who progress radiologically according to RECIST v1.1, but who are deemed by the 
Investigator to be clinically benefiting from study medication may continue that study 
medication at the discretion of the Investigator; a PD confirmatory scan will be done at least 
6 weeks after the last scan to identify potential pseudo-progression according to iRECIST (56) 
(Appendix 4 Summary of iRECIST Guidelines). If progression is not confirmed, tumor 
reassessment should continue as originally planned according to the Study Schedule.  
Post-baseline scans will include: 
• 
CT/MRI scan of the chest, abdomen, and pelvis. 
• 
CT/MRI scan of any other sites of disease as identified at Baseline. 
• 
Clinical assessment of sites of superficial disease identified at Baseline. Clinical 
assessment of superficial disease must coincide with the imaging studies and will 
include photographs of all superficial metastatic lesions. All lesion measurements 
must be recorded in the eCRF. 
• 
Bone scans will be performed at the discretion of the Investigator (e.g. to confirm CR, 
to follow up existing metastases, or if [based on signs and symptoms] new bone 
metastases are suspected). Any suspicious abnormalities (i.e. hotspots) will be 
confirmed by X-ray, CT scan or MRI (if applicable, using the same method used to 
confirm the bone lesions at Baseline).  
• 
Brain CT/MRI is only required if signs and symptoms suggest the presence of 
metastatic brain disease or if the patient has a history of stable metastatic brain 
disease (Section 5.1).  
8.2.3 
Further Information for CT/MRI Scans 
CT scans, including brain CT scan if applicable, should be performed with contrast agents 
unless contra-indicated for medical reasons. If IV contrast is medically contra-indicated, the 
imaging modality to be used to follow the disease (either CT without contrast or MRI) should 
be the modality which best evaluates the disease, and the choice should be determined by 
the Investigator in conjunction with the local radiologist. MRI of the abdomen and pelvis can 
be substituted for CT if MRI adequately depicts the disease. However, MRI of the chest should 
not be substituted for CT of chest even if IV contrast is contra-indicated. In such cases, CT will 
be performed without contrast. If MRI is used to follow-up bone lesion(s), it must be performed 
a few days before any treatment that may affect bone-marrow cellularity (e.g. G-CSF). 
The same method and technique should be used to characterize each lesion identified and 
reported at Baseline, during the study treatment phase, and during follow-up. The use of plain-
film X-rays (with the exception of bone X-rays) is discouraged. The use of positron emission 
tomography (PET) imaging as the only imaging modality is not permitted. 
For patients having effusions or ascites, cases having cytological proof of malignancy should 
be recorded as non-target lesions on the tumor assessment eCRFs. Effusions that have not 
been evaluated using cytology or were found to be non-malignant should not be recorded on 
the non-target lesion CRF. 
8.3 
Efficacy Parameters 
The evaluation of disease response will be conducted according to RECIST v1.1 guidelines.  
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8.3.1 
Progression Free Survival 
The primary efficacy variable for this study is time to PFS, based on an assessment by the 
IRC. A supportive analysis of PFS will be performed based on the local Investigator's review.  
PFS is defined as the time from the date of randomization to the earliest evidence of 
documented PD or death from any cause.  
8.3.2 
Overall Survival  
OS is defined as the time from date of randomization in this study to date of death due to any 
cause. Patients without a death date will be censored at the date the patient was last known 
to be alive.  
The Investigator will monitor the patient for OS status, for the remainder of the study period, 
as described in Section 7.  
8.3.3 
Objective Response Rate  
ORR is defined as the proportion of patients with a confirmed CR + confirmed PR. The ORR 
will be assessed according to RECIST v1.1 guidelines by the IRC and by the local 
Investigator's review and will be based on the best response assessed.  
8.3.4 
Time to Response 
Time to response is defined as the time from date of randomization to the time of first 
documented CR or PR as assessed by the IRC and by the local Investigator's review.  
8.3.5 
Duration of Response 
Duration of response is defined as the time from first documented CR or PR until the earliest 
evidence of disease progression or death from any cause based on the IRC review and the 
local Investigator's review.  
8.3.6 
Clinical Benefit Rate 
CBR is defined as the proportion of patients with confirmed CR, confirmed PR, or SD for 
≥6 months. The CBR will be assessed according to RECIST v1.1 guidelines by the IRC and 
by the local Investigator's review. CBR will be compared between the treatment arms using 
logistic regression as described for ORR. Exact Clopper Pearson 2-sided 95% confidence 
limits will be calculated for the CBR of each treatment arm. 
8.3.7 
Disease Control Rate 
DCR is defined as the number of patients with confirmed CR, confirmed PR, or SD. The DCR 
will be assessed according to RECIST v1.1 guidelines by the IRC and by the local 
Investigator's review. 
9. 
ASSESSMENT OF SAFETY  
9.1 
Safety Assessments 
Safety assessments will consist of monitoring all AEs, including SAEs (Section 9.2), regular 
monitoring of hematology, serum chemistry (Section 9.9), renal function, liver function, ECGs 
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(Section 9.8), physical examinations (Section 9.6), vital signs (Section 9.7), and ECOG 
performance status (Section 9.6). 
Comprehensive assessment of any apparent AE experienced by the patient will be performed 
throughout the course of the study, from the time that the patient receives the first dose of 
study medication until 30 days after the last study drug administration; SAEs will be recorded 
from the date that the ICF is signed.  
Study site personnel will report any AE, whether observed by the Investigator or reported by 
the patient.  
AE assessment will include type, incidence, severity (graded by National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] version 5.0, see 
Section 9.2.3, Severity Assessment), timing, seriousness, and relatedness. 
 
Adverse Events of Particular Interest and Adverse Events of Special Interest 
AEPIs include all events of special interest and additionally, all events for which a separate 
analysis will be performed (Table 9). 
AEPIs are based on the emerging AE profile of balixafortide or on the established risks 
associated with eribulin.  
All grade events of thrombocytopenia, peripheral neuropathy, hepatic impairment and QTc 
interval prolongation have been identified as AEPIs.  
Serious events of IRRs, neutropenia and infection, and all cases of renal impairment will be 
considered AESIs, as well as being AEPIs.  
AESIs are to be reported by the Investigator to the Sponsor within 24 hours of learning of the 
event. 
AESIs must be reported using the same form as for SAEs and notified to the Sponsor within 
24 hours of the Investigator becoming aware of the event, irrespective of causality with the 
study drug. 
 
 
 
 
 
 
 
 
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Table 9 
AEs of Particular Interest and AEs of Special Interest 
Adverse Events of 
Particular Interest 
Definition 
Thrombocytopenia 
Defined using SMQ “Haematopoietic Thrombocytopenia narrow”. SMQ code 
20000031 
Peripheral neuropathy 
Defined using SMQ “Peripheral neuropathy narrow” SMQ code 20000034 
Hepatic impairment 
Defined using SMQ “Liver related investigations, signs and symptoms (SMQ) 
narrow” SMQ code 20000008 
QTc prolongation 
Defined using SMQ “Torsade de pointes/QT prolongation “SMQ code 
20000001 
Hypersensitivity/IRRs 
IRRs are defined as AEs that are deemed related to any study treatment by 
the Investigator, which occurred during infusion or within 24 hours from the 
end of infusion. 
Note: IRRs encompass AEs reported as the MedDRA PT “Infusion 
related reaction” (within the SOC “Injury, Poisoning and Procedural 
Complications”) together with reported signs and symptoms of IRRs 
Neutropenia (serious)  
Based on reported AEs rather than laboratory values. Defined using SMQ 
“Haematopoietic Cytopenia” SMQ code 20000027 
Neutropenic infections 
Defined by PT neutropenic infection  
Febrile neutropenia 
Defined by the PT febrile neutropenia 
Renal impairment 
Defined using SMQ “Acute renal failure” SMQ code 20000003 
Adverse Event of Special 
Interest 
Definition 
Hypersensitivity/IRRs (serious) 
IRRs are defined as AEs that are deemed related to any study treatment by 
the Investigator, which occurred during infusion or within 24 hours from the 
end of infusion. 
Note: IRRs encompass AEs reported as the MedDRA PT “Infusion related 
reaction” (within the SOC “Injury, Poisoning and Procedural Complications”) 
together with reported signs and symptoms of IRRs 
Neutropenia (serious) 
Based on reported AEs rather than laboratory values 
Neutropenic infections 
Defined by PT neutropenic infection  
Febrile neutropenia 
Defined by the PT febrile neutropenia 
Renal impairment 
Defined using SMQ “Acute renal failure” SMQ code 20000003 
AE: adverse event; IRR: infusion-related reaction; MedDRA: Medical Dictionary for Regulatory Activities; PT: 
preferred term; QTc: corrected QT interval; SMQ: Standardized MedDRA query; SOC: system order class.   
Baseline tumor-related signs and symptoms will be recorded at the Cycle 1, Day 1 visit and 
then reported as AEs (Section 9.2.5) during the study if they worsen in severity or increase in 
frequency. 
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9.2 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the study drug(s) must be reported as described in the following sections. 
For all AEs, the Investigator must pursue and obtain information adequate both to determine 
the outcome of the AE, and to assess whether it meets the criteria for classification as a SAE 
requiring immediate notification to the Sponsor. Where possible, a diagnosis rather than a list 
of symptoms should be recorded. If a diagnosis has not been made, then each symptom 
should be listed individually. For all AEs, sufficient information should be obtained by the 
Investigator to determine the causality of the AE. The Investigator is required to assess 
causality. Follow-up by the Investigator may be required until the event or its sequelae resolve 
or stabilize at a level acceptable to the Investigator, and the Sponsor concurs with that 
assessment. 
If a patient opts to discontinue from the treatment phase because of an unacceptable AE, 
"Withdrawal of Consent" must not be the reason for discontinuation, rather, the reason for 
discontinuation must be recorded as "Unacceptable Toxicity". Details of the AE leading to the 
patient’s withdrawal of consent and the action taken must be completed on the AE CRF. AEs 
must be reported in accordance with the reporting requirements defined in Section 9.2.5.  
9.2.1 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation of a patient 
administered a pharmaceutical product, 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 product, whether or not considered related to the medicinal product. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure 
is considered the AE rather than the procedure itself. 
Examples of AEs include but are not limited to: 
• 
Clinically significant signs and symptoms. 
• 
Changes in physical examination findings. 
• 
Abnormal test results. 
• 
Signs and symptoms resulting from circumstances such as drug overdose, misuse, 
interaction, exposure during pregnancy, medication errors or occupational exposure. 
• 
Hypersensitivity. 
Pre-existing conditions 
Medical conditions that present at Screening, and do not worsen in severity or frequency 
during the study, are defined as Baseline Medical Conditions and are NOT to be considered 
AEs. Findings discovered during Screening must be recorded as part of Medical History and 
any pre-planned intervention or procedure to occur during the study recorded in the patient’s 
source data and eCRF. 
Malignancy under study 
Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section of the patient’s source data and eCRF; tumor assessments may be 
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done at any time if there is clinical suspicion of disease progression (Section 8.2.2). Disease 
progression assessed by measurement of malignant lesions on radiographs or other methods 
should not be reported as AEs. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g. on an ECG 
trace) should not be reported as AEs unless they are clinically meaningful or associated with 
clinical signs and symptoms, lead to treatment discontinuation or are considered otherwise 
medically important by the Investigator. If an abnormality fulfils these criteria, the identified 
medical condition (e.g. anemia, hepatitis) must be reported as the AE rather than the abnormal 
value itself. 
9.2.2 
Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that: 
• 
Results in death. 
• 
Is life-threatening (immediate risk of death). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions). 
• 
Results in congenital anomaly/birth defect. 
• 
Is otherwise considered as medically important. 
The term “life-threatening” in this definition refers to an event in which the patient is at risk of 
death at the time of the event; it does not refer to an event that hypothetically might cause 
death if it were more severe. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, 
they may jeopardize the patient or may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. 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 patient hospitalization, or the development of 
drug dependency or drug abuse. 
Hospitalization 
Hospitalization is defined as initial admission in a hospital or similar healthcare facility, or any 
prolongation of an existing hospitalization. Hospitalization (or prolongation of hospitalization) 
in the absence of a precipitating, clinical AE is not in itself an SAE. An emergency room visit 
does not necessarily constitute a hospitalization; however, the event leading to the emergency 
room visit should be assessed for medical importance. Pre-planned treatments or surgical 
procedures should be noted in the baseline documentation for the entire protocol and/or for 
the individual patient. 
Progression of malignancy under study 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the safety reporting period 
(see Section 9.2.5.1). Hospitalization due to signs and symptoms of disease progression 
should not be reported as an SAE. If the malignancy has a fatal outcome during the study or 
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within the safety reporting period, then the event leading to death must be recorded as an AE 
and as an SAE with NCI CTCAE Grade 5 in the patient’s source data and eCRF (see 
Section 9.2.3). 
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
Investigator to provide clarity and understanding of the event in the context of the clinical trial. 
9.2.3 
Severity Assessment 
The Investigator will report AEs using concise medical terminology (verbatim) as well as the 
appropriate severity graded according to NCI CTCAE version 5.0 on the patient’s source data 
and eCRF and will use the following definitions of severity to describe the maximum intensity 
of the AE: 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• 
Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)1. 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL2. 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE.  
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example, a headache may be severe (interferes significantly with the 
patient's usual function), but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above. 
9.2.4 
Causality Assessment 
Investigators must also systematically assess the causal relationship of AEs to the study drugs 
using the following definitions. Decisive factors for the assessment of causal relationship of 
an AE to the study medications include, but may not be limited to, temporal relationship 
between the AE and the study medications, known side effects of trial treatments, medical 
history, concomitant medication, course of the underlying disease, study procedures. 
• 
Not related: Not suspected to be reasonably related to the study medications. AE 
could not medically (pharmacologically/clinically) be attributed to the study medications 
under study in this clinical trial protocol. A reasonable alternative explanation must be 
available. 
                                            
1 Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
2 Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden 
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• 
Related: Suspected to be reasonably related to the study medications. AE could 
medically (pharmacologically/clinically) be attributed to the study drug under trial in this 
clinical study. 
If the Investigator’s causality assessment is unknown but not related, this must be clearly 
documented on study records, including the patient’s source data and eCRF. If the Investigator 
does not know whether or not the study drug caused the event, then the event will be 
conservatively handled as “related” to the study drug. 
In addition, if the Investigator determines an SAE is associated with study procedures, the 
Investigator must record this causal relationship in the source documents and the patient’s 
source data and eCRF, as appropriate, and report such an assessment in accordance with 
the SAE reporting requirements, if applicable. 
9.2.5 
Reporting Requirements 
9.2.5.1 Serious Adverse Event Reporting  
For SAEs, the active reporting period to Sponsor begins from the time that the patient provides 
informed consent, which is obtained prior to the patient’s participation in the study (i.e. prior to 
undergoing any study-related procedure and/or receiving study drug) through and including 
30 calendar days after the last administration of the study drug.  
If an SAE occurs, the Sponsor is to be notified within 24 hours of the Investigator becoming 
aware of the event. In particular, if the SAE is fatal or life-threatening, notification to the 
Sponsor must be made immediately, irrespective of the extent of available AE information. 
This timeframe also applies to additional new information (follow-up) on previously forwarded 
SAE reports, as well as to the initial and follow-up reporting of exposure during pregnancy, 
exposure via breastfeeding and occupational exposure cases. 
For all SAEs, the Investigator is obligated to pursue and provide information to the Sponsor in 
accordance with the timeframes for reporting specified above. In addition, an Investigator may 
be requested by the Sponsor to obtain specific additional follow-up information in an expedited 
fashion. This information collected for SAEs is more detailed than that captured on the 
patient’s AE source data and eCRF. In general, this will include a description of the AE in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, such 
as concomitant medications, vaccines, and/or illnesses must be provided. In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to the Sponsor. 
SAEs occurring to a patient after the active reporting period has ended should be reported to 
the Sponsor if the Investigator becomes aware of them; at a minimum, all SAEs that the 
Investigator believes have at least a reasonable possibility of being related to study drug are 
to be reported to the Sponsor. 
9.2.5.2 Non-Serious Adverse Event Reporting 
AEs must be recorded on the patient’s source data and eCRF from the time the patient has 
taken at least one dose of study drug through to the patient’s safety follow-up visit at 30 days 
(±7 days) after the last dose of study drug. AEs should be reported using concise medical 
terminology. Where possible, a diagnosis rather than a list of symptoms should be recorded. 
If a diagnosis has not been made, then each symptom should be listed individually. 
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All events should be followed to their resolution, until the Investigator assesses them as stable, 
irreversible, or until the patient is lost to follow-up, whichever comes first. If a patient begins a 
new systemic anti-cancer therapy, the AE reporting period for non-SAEs ends at the time the 
new treatment is started. 
9.2.5.3 Safety Reporting to Health Authorities, Independent Ethics Committees/ 
Institutional Review Boards and Investigators 
The Sponsor will conduct appropriate safety reporting to Health Authorities in accordance with 
applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (and in particular deaths) involving his/her patients to the IEC/IRB that 
approved the study. 
In accordance with ICH GCP guidelines, the Sponsor will inform the Investigator of “findings 
that could adversely affect the safety of patients, impact the conduct of the study or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the study.” In particular, and in line with 
respective regulations, the Sponsor will inform the Investigator of AEs that are both serious 
and unexpected and are considered to be related to the administered product (“suspected 
unexpected serious adverse reactions” or SUSARs). The Investigator must place copies of 
Safety Reports in the Investigator Site File (ISF). National regulations with regard to Safety 
Report notifications to Investigators will be taken into account. 
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety Reports directly to the concerned lead IEC/IRB and will maintain records of these 
notifications. When direct reporting by the Sponsor is not clearly defined by national or site-
specific regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety Reports provided by the Sponsor and of filing copies of all related 
correspondence in the ISF. 
For studies covered by the European Commission legislation the Sponsor responsibilities will 
be carried out in accordance with the applicable legislation. 
9.2.6 
Monitoring and Management of AESIs and AEPIs 
9.2.6.1 Potential Cases of Drug-induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver injury 
are considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and 
should always be considered important medical events. 
• 
Patients with baseline AST or ALT and total bilirubin values within the normal range 
who subsequently present with AST or ALT values ≥3x ULN concurrent with a total 
bilirubin value ≥2x ULN with no evidence of hemolysis and an alkaline phosphatase 
(ALP) value ≤2x ULN or not available. 
• 
For patients with pre-existing ALT or AST or total bilirubin values above the ULN, the 
following threshold values should be used in the definition mentioned above: 
o For patients with pre-existing baseline AST or ALT values above the normal range: 
AST or ALT values ≥2x the baseline values and ≥3x ULN, or ≥8x ULN (whichever 
is smaller). 
• 
For patients with pre-existing values of total bilirubin above the normal range:  
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o Total bilirubin level increased from baseline by an amount of at least 1x ULN or if 
the value reaches ≥3x ULN (whichever is smaller). 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase (CK), total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time/international normalized ratio (INR), and ALP. A detailed 
history, including relevant information, such as review of ethanol, acetaminophen, recreational 
drug and supplement consumption, family history, occupational exposure, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history of 
liver or allergic disease, and work exposure, should be collected. 
Further testing for acute hepatitis A, B, or C infection and liver imaging (e.g., biliary tract) may 
be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria defined 
above, with no other cause for liver function test (LFT) abnormalities identified at the time 
should be considered potential Hy’s Law cases irrespective of availability of all the results of 
the investigations performed to determine etiology of the abnormal LFTs. Such potential Hy’s 
Law cases must be reported as SAEs (see Section 9.2.5.1). 
9.2.6.2 QT Prolongation  
In the event of a QT prolongation, possible alternative reversible causes such as serum 
electrolyte abnormalities, or concomitant medications with the potential to prolong the QT 
interval (Appendix 1 Prohibited Medications) should be evaluated. If such reversible causes 
are identified, they should be corrected accordingly (i.e. correction of electrolyte abnormalities 
with supplements to within normal limits and/or discontinuation of concomitant medications 
known to prolong the QT interval). 
At the first occurrence of a QTc interval >480 msec and ≤500 msec (Grade 2), Investigators 
should identify and treat alternative reversible causes and initiate more frequent ECG 
monitoring according to the Investigator’s best medical judgement until QTc ≤480 msec. 
Dosing of the study drug can continue. However, if the QTc interval remains >480 msec or 
reoccurs in the absence of alternative causes or despite their correction, specialist cardiologist 
consultation should be arranged, and treatment continuation discussed with the cardiologist 
and Medical Monitor. 
If at any time the mean QTcF is prolonged (≥501 msec on at least two separate ECGs, [i.e. 
CTCAE Grade ≥3]), then the ECGs should be re-evaluated by a qualified person at the site 
for confirmation as soon as the finding is made, including verification that the machine reading 
is accurate. If manual reading confirms a QTc of ≥501 msec, immediate search for reversible 
causes (including electrolyte abnormalities, and concomitant medications for drugs with the 
potential to prolong the QT interval [see Appendix 1 Prohibited Medications]) must be 
performed.  
If QTc interval reverts to <501 msec, and, in the judgment of the Investigator(s) in consultation 
with the Sponsor, the cause is determined to be due to cause(s) other than study drugs, 
treatment may be continued with appropriate ECG monitoring. 
If a prolonged QTcF interval >501 msec is confirmed, study drug will be held until the QTc 
interval decreases to <501 msec. 
Prior to concluding that an episode of prolongation of the QTc interval is due to study drug, 
thorough consideration should be given to potential precipitating factors (e.g. change in patient 
clinical condition, effect of concurrent medication, electrolyte disturbance) and possible 
evaluation by a specialist. 
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Events of QT prolongation >480 msec, or otherwise considered clinically significant, must be 
reported as AEs.  
9.2.6.3 Infusion-Related Reactions 
Acute IRRs and hypersensitivity events due to histamine release, such as rash, pruritus, 
erythema and flushing may occur. The majority of hypersensitivity events in the earlier studies 
occurred during first administration and were generally dose dependent.  
All patients should be observed during the infusion of balixafortide and recommended dosage 
and infusion duration closely adhered to. An antihistamine kit must be kept available for 
immediate intervention in case of IRRs. Prophylactic use of H1 receptor antagonists may be 
used for premedication at the discretion of the treating physician. 
For management of IRRs: 
• 
The balixafortide infusion should be interrupted and vital signs monitored until the IRR 
resolves to Grade ≤1 and then the infusion can be restarted at a slower rate. 
• 
Treatment with antihistamines and methylprednisolone can be initiated, or other 
treatments can be given as necessary in line with the patient’s condition and local 
standard of care.  
• 
The patient can be pre-treated with antihistamines prior to the next balixafortide 
infusion. 
• 
If the IRR continues, the balixafortide infusion rate can be slowed down to 3 hours and 
if not resolved, the Sponsor contacted. 
When anaphylaxis is suspected and/or confirmed, treatment with epinephrine must be initiated 
immediately. In case of severe reactions, the infusion of balixafortide should be stopped 
immediately and treatment discontinued permanently. 
AEs of IRRs and hypersensitivity must be captured on the patient’s source data and AE eCRF 
page, along with their signs and symptoms. If dosing is interrupted, discontinued or the patient 
is withdrawn from the study as a result of an infusion site reaction, this must be recorded in 
the patient’s source data and eCRF. 
9.2.6.4 Neutropenia 
Risk factors for febrile neutropenia in addition to those posed by eribulin and advanced BC 
are shown in Table 10. From Day 2, Cycle 1, this study requires adherence to the ASCO 
guidelines for minimizing the incidence of febrile neutropenia, including the recommended 
prophylactic use of CSFs, where appropriate at the discretion of the Investigator (Appendix 7 
ASCO Guidance on the Use of CSFs) (54). 
 
 
 
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Table 10 
Patient Risk Factors for Febrile Neutropenia 
Risk Factora 
Age ≥65 years 
Advanced disease 
Previous chemotherapy or radiation therapy  
Pre-existing neutropenia or bone marrow involvement with tumor infection 
Open wounds or recent surgery 
Poor performance status or poor nutritional status 
Poor renal function 
Liver dysfunction, most notably elevated bilirubin 
Cardiovascular disease  
Multiple comorbid conditions 
HIV infection 
HIV: human immunodeficiency virus 
Source: (54) 
a: When estimating a patient's overall risk of febrile neutropenia, consider these risk factors in addition to those 
posed by eribulin and advanced breast cancer. 
 
Severe neutropenia (ANC<500/mm3) lasting more than 1 week occurred in 12% of patients 
who received eribulin in the EMBRACE study, leading to discontinuation in <1% of patients 
(43). The mean time to nadir was 13 days and the mean time to recovery from severe 
neutropenia with eribulin was 8 days. Febrile neutropenia occurred in 5% of patients treated 
with eribulin. 
Patients with ALT or AST >3x ULN experienced a higher incidence of Grade 4 neutropenia 
and febrile neutropenia with eribulin than patients with normal aminotransferase levels. 
Patients with bilirubin >1.5x ULN also had a higher incidence of Grade 4 neutropenia and 
febrile neutropenia with eribulin.  
If the ANC is <1000/mm3, refer to guidance on dose modifications and interruptions with 
eribulin in Section 6.1.2. 
Local guidance on management of neutropenic infections should be consulted. Guidance on 
outpatient management of fever and neutropenia in patients treated for malignancy is provided 
by ASCO (57).      
 
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9.2.6.5 Thrombocytopenia 
Guidance on platelet transfusions in patients with cancer is provided by ASCO (58). 
9.2.6.6 Peripheral Neuropathy 
Grade 3 and Grade 4 peripheral neuropathy occurred in 8% and 0.4% of patients who 
received eribulin respectively (43). Peripheral neuropathy led to discontinuation of eribulin in 
5% of patients and neuropathy lasting more than 1 year occurred in 5% of patients. 
Patients should be monitored closely for signs of peripheral motor and sensory neuropathy. If 
Grade 3 or 4 peripheral neuropathy develops, refer to guidance on dose modifications and 
interruptions with eribulin in Section 6.1.2. 
9.2.6.7 Renal Impairment 
If renal function changes or worsens under treatment with balixafortide, a review of all 
medication and medical conditions potentially contributing to renal impairment should be done. 
Standard medical care principals should be applied to stabilize kidney function (e.g. fluid 
management and the use of diuretics if appropriate). 
9.3 
Exposure During Pregnancy  
An exposure during pregnancy occurs if a female becomes, or is found to be, pregnant either 
while receiving or having been exposed (e.g. because of treatment or environmental 
exposure) to the study drugs; or the female becomes, or is found to be, pregnant after 
discontinuing and/or being exposed to the study drugs. An example of environmental exposure 
would be a case involving direct contact with a study product in a pregnant woman (e.g. a 
nurse reports that she is pregnant and has been exposed to chemotherapeutic products). 
If a study patient or study patient’s partner becomes, or is found to be, pregnant during the 
study patient’s treatment with the study drugs, the Investigator must submit this information to 
the Sponsor on the Pregnancy Reporting Form, regardless of whether an AE or SAE has 
occurred. In addition, the Investigator must submit information regarding environmental 
exposure to a study product in a pregnant woman (e.g. a patient reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the designated 
Pregnancy Reporting Form. This must be done irrespective of whether an AE has occurred 
and within 24 hours of awareness of the exposure. The information submitted should include 
the anticipated date of delivery (see below for information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all 
in utero exposure reports with an unknown outcome. The Investigator will follow the pregnancy 
until completion (or until pregnancy termination) and notify the Sponsor of the outcome as a 
follow-up to the initial pregnancy report. In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth. In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (i.e. ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator must follow the procedures for reporting SAEs. 
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In the event of a pregnancy in a patient occurring during the course of the study, the patient 
must be discontinued from study medication immediately. The Sponsor must be notified 
without delay and the patient must be followed up as mentioned above. 
9.4 
Medication Errors 
A medication error is an unintended failure in the drug treatment process that leads to, or has 
the potential to lead to, harm to the patient. Medication errors may result from administration 
or consumption of the study drug(s) by the wrong patient, wrong time or at the wrong strength. 
Medication errors include medication errors involving patient exposure to the study drug, as 
well as potential medication errors or uses outside what is foreseen in the protocol that do, or 
do not involve the study patient. 
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error is captured on the medication error version of the patient’s 
source data and eCRF page and, if applicable, any associated AE(s) are captured on the 
patient’s source data and eCRF. In the event of an SAE resulting from a medication error, the 
Sponsor must be notified immediately in alignment with the SAE reporting process (see 
Section 9.2.5.1). 
9.5 
Occupational Exposure 
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
study product, which may or may not lead to the occurrence of an AE. 
An occupational exposure is reported to the Medical Monitor within 24 hours of the 
Investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a Case Report Form (CRF); however, a copy of the 
completed SAE Report form must be maintained in the ISF. 
9.6 
Physical Examination 
A standard, complete physical examination will include an examination of all major body 
systems (including general appearance, head, ears, eyes, nose, mouth, throat, neck, thyroid, 
lungs, heart, breasts, abdomen, and musculoskeletal), height (at Screening only), weight, BP, 
and pulse rate; it may be performed by a physician, registered nurse or other qualified health 
care provider (as delegated in the Study Site Log). 
A targeted physical examination will include an examination of general appearance, skin 
(including presence of rash), lungs and heart, extremity examination for the presence of 
peripheral edema, abdominal if relevant, neurologic (particularly motor and sensory function, 
coordination), and lymph nodes in addition to specific areas of interest based on sites of 
disease. 
A standard, complete physical examination will be performed in all patients at Screening. 
A targeted physical examination will be performed on Day 1 of each cycle for patients on the 
balixafortide + eribulin treatment arm and on Day 2 of each cycle for patients on the eribulin 
monotherapy treatment arm. The assessment should be done prior to administration of study 
medication. 
A targeted physical examination will also be performed in all patients at the EoT visit.   
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Additional physical examinations to those scheduled for this study should be performed as 
indicated at the Investigator’s discretion (e.g. due to concerns about patient safety, patient’s 
clinical status); the findings of an unscheduled physical examination should be recorded in the 
patient's source data and eCRF.  
Height will be assessed and recorded in all patients at Screening only.  
Weight will be assessed in all patients at Screening and at the EoT visit. Weight will also be 
assessed on Day 1 of each cycle for patients on the balixafortide + eribulin treatment arm and 
on Day 2 of each cycle for patients on the eribulin monotherapy treatment arm. The 
assessment should be done prior to administration of study medication. 
Furthermore, during physical examinations, special attention should be paid to the 
development of any signs of peripheral neuropathy that could warrant eribulin dose 
modifications or delays as described in Sections 6.1.2 and 6.1.2.1. 
 
ECOG Performance Status Assessment 
To be eligible for entry into this study, patients must have an ECOG Performance Status of 
0-2 at Screening. The ECOG Performance Status will be recorded in all patients at the 
Screening Visit and at the EoT visit.  
The ECOG Performance Status will also be recorded on Day 1 of each treatment cycle in 
patients on the balixafortide + eribulin treatment arm and on Day 2 of each cycle for patients 
on the eribulin monotherapy treatment arm. (The assessment should be done prior to 
administration of study medication).  
The ECOG Performance Status assessment is provided in Appendix 2 ECOG Performance 
Status.  
9.7 
Vital Signs 
Body temperature, resting BP, respiratory rate, and pulse rate will be measured and recorded 
as vital signs.   
Vital signs will be assessed in all patients at Screening, and at the EoT visit.  
Vital signs will also be assessed on Day 1 of each cycle for patients on the balixafortide + 
eribulin treatment arm and on Day 2 of each cycle for patients on the eribulin monotherapy 
treatment arm. The assessment will be done prior to administration of study medication. 
Additional measures of vital signs to those scheduled for this study should be performed as 
indicated at the Investigator's discretion (e.g. due to concerns about patient safety, patient's 
clinical status); the findings of an unscheduled assessment should be recorded in the patient's 
source data and eCRF. 
Vital signs measured in the event of an infusion reaction should also be recorded in the 
patient's source data and eCRF.   
BP will be measured in the patient’s arm and recorded to the nearest mmHg. The same arm 
and position should be used throughout the study, using an appropriate cuff size. All BP 
readings should be measured in the supine position after resting for at least 5 minutes. When 
the timing of these measurements coincides with blood collection, the BP and heart rate 
should be obtained first.  
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Any clinically relevant abnormalities in vital signs at Screening must be handled as 
Pre-existing Conditions as outlined in Section 9.2.1.  
9.8 
12 Lead Electrocardiogram 
An ECG will be performed at the clinical site during the visits and timepoints shown in Table 11. 
Table 11 
ECG Schedule 
Treatment Arm 
Visit  
Day 
ECG Timepoint 
ECG Type 
All 
Screening 
-21 to -1 
Anytime 
12-lead 
Balixafortide 
+ 
eribulin 
Cycle 1 
1 
Within 1 hour prior to administration of 
balixafortide 
Duplicate 
12-
lead 
Balixafortide 
+ 
eribulin 
Cycle 1 
2 
Immediately before starting the balixafortide 
infusion 
12-lead 
Eribulin 
monotherapy  
Cycle 1 
2 
Immediately before starting the eribulin infusion 
12-lead 
All 
Cycle 1 
2 
Within 1 hour after completing the eribulin 
infusion 
12-lead 
Balixafortide 
+ 
eribulin 
Cycle 1 
9 
Immediately before starting the balixafortide 
infusion 
12-lead 
Eribulin 
monotherapy  
Cycle 1 
9 
Immediately before starting the eribulin infusion 
12-lead 
All 
Cycle 1 
9 
Within 1 hour after completing the eribulin 
infusion 
12-lead 
Balixafortide 
+ 
eribulin 
Cycle 
2 
& 
subsequent 
cyclesa 
2 
Immediately before starting the balixafortide 
infusion 
12-lead 
Eribulin 
monotherapy  
Cycle 
2 
& 
subsequent 
cyclesa 
2 
Immediately before starting the eribulin infusion 
12-lead 
All 
Cycle 
2 
& 
subsequent 
cyclesa 
2 
Within 1 hour after completing the eribulin 
infusion 
12-lead 
Balixafortide 
+ 
eribulin 
Cycle 
2 
& 
subsequent 
cyclesa 
9 
Immediately before starting the balixafortide 
infusion 
12-lead 
Eribulin 
monotherapy  
Cycle 
2 
& 
subsequent 
cyclesa 
9 
Immediately before starting the eribulin infusion 
12-lead 
All 
Cycle 
2 
& 
subsequent 
cyclesa 
9 
Within 1 hour after completing the eribulin 
infusion 
12-lead 
All 
EoT 
- 
Anytime 
12-lead 
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a: After Cycle 2, the frequency of ECG recordings can be reduced to every 2 cycles if deemed clinically appropriate (i.e. absence 
of ECG findings in earlier assessments). 
Additional ECGs can be performed as clinically indicated at any time and the results recorded 
in the source data and eCRF. 
All ECGs will be performed using a 12-lead (with a 10-second rhythm strip) tracing. ECG 
measurements will include PR interval, QT interval, QTcF interval, RR interval, and QRS 
complex. It is preferable that the machine used has a capacity to calculate the standard 
intervals automatically. 
ECG interval readings by the ECG recorder’s algorithm will be read and interpreted at the 
investigational site for eligibility determination and patient safety monitoring and 
documentation stored in the source documents.  
Patients should be supinely resting for at least 10 minutes before and 5 minutes after 
timepoints for ECG recordings. When the timing of the ECG coincides with blood collection, 
the ECG should be obtained first. During treatment, ECGs will be compared to Screening or 
most recent ECG and any clinically significant changes will be recorded as AEs and evaluated 
further, as clinically warranted. Episodes of QT prolongation should be managed as described 
in Section 9.2.6.2. 
9.9 
Clinical Laboratory Evaluations 
Analysis of clinical laboratory samples will be conducted locally. The following parameters will 
be analyzed for the clinical laboratory tests: 
• 
Hematology – WBC count with differential, red blood cell (RBC) count, hemoglobin 
(Hb), hematocrit (Ht), platelet count.  
• 
Chemistry – albumin, total protein, ALT, AST, total bilirubin, GGT, ALP, glucose, 
creatinine, blood urea nitrogen (BUN), CK, calcium (Ca), potassium (K), sodium (Na), 
and magnesium (Mg).  
• 
Urinalysis – appearance, color, dipstick (pH, gravity, ketones, protein, glucose, blood, 
bilirubin, nitrite, leukocytes). Microscopic analysis if warranted by Dipstick results. 
Abnormal laboratory test results considered to be clinically significant shall be recorded as an 
AE in the patient's source data and eCRF (Section 9.2.1) and the patient will be followed-up 
until the laboratory value has returned to normal range or stabilized at a non-clinically 
significant value.  
Any additional blood tests to those scheduled in this study should be performed as indicated 
at the Investigator's discretion (e.g. due to concerns about patient safety, patient's clinical 
status); the findings of an unscheduled test should be recorded in the patient's source data 
and eCRF.  
10. 
PHARMACOKINETIC ASSESSMENT 
Blood samples will be collected only for the balixafortide + eribulin treatment arm to: 
• 
Evaluate the PK of balixafortide and its metabolite levels in patients on the balixafortide + 
eribulin treatment arm. 
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• 
Support the data from the immunogenicity assessment by evaluating the PK of 
balixafortide.  
Details on sample collection, processing and shipment to Central Laboratories will be provided 
in a separate laboratory manual. 
10.1 
Balixafortide + Eribulin treatment arm 
For patients who receive eribulin + balixafortide, the blood samples will be taken in relation to 
the timing of the balixafortide infusion. Blood samples that are to be taken: 
• 
Immediately before starting the balixafortide infusion will ideally be taken within 
0−30 minutes before starting the balixafortide infusion. 
• 
Immediately after completing the balixafortide infusion will ideally be taken within 
0−15 minutes after completing the balixafortide infusion. 
The times at which all blood samples are taken should be documented precisely; this is 
mandatory for the samples taken during the 1−20 hours timeframe and also the pre and post-
dose balixafortide samples. 
Blood samples will be collected from all patients on the balixafortide + eribulin treatment arm 
at the visits and timepoints shown in Table 12. 
Table 12 
Schedule for Pharmacokinetic Assessments of All Patients in the 
Balixafortide + Eribulin Treatment Arm  
Visit Cycle 
Day 
Timepoint 
1 
2 
Immediately before starting the infusion of balixafortide 
1 
2 
Immediately after completing the infusion of balixafortide 
1 
2 
One additional sample scheduled flexibly with precise recording, at 1−20 hours 
after completing the infusion of balixafortide on Day 2 
1 
8a 
Immediately after completing the infusion of balixafortide 
1 
9a 
Immediately before starting the infusion of balixafortide 
2 
2a 
Immediately after completing the infusion of balixafortide 
2 
8a 
Immediately after completing the infusion of balixafortide 
2 
9a 
Immediately before starting the infusion of balixafortide 
3 
2 
Immediately before starting the infusion of balixafortide 
3 
2 
Immediately after completing the infusion of balixafortide 
5 
2a 
Immediately after completing the infusion of balixafortide 
5 
3a 
Immediately before starting the infusion of balixafortide 
7 
2a 
Immediately after completing the infusion of balixafortide 
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7 
3a 
Immediately before starting the infusion of balixafortide 
a: Primarily to support the data from the immunogenicity assessment and used to evaluate the PK of balixafortide 
and its metabolites. 
Additional PK samples, taken up to 48 hours after the last dose in approximately 15 patients, 
will allow monitoring of drug clearance after dosing has ceased. Therefore, blood samples will 
be collected from patients at selected sites at the visits and timepoints shown in Table 13.  
 
Table 13 
Schedule for Pharmacokinetic Assessments of Patients at Selected Sites in 
the Balixafortide + Eribulin Treatment Arm 
Visit Cycle 
Day 
Timepoint 
3 
4 
24 hours (±4 hours) after completing the balixafortide infusion on Day 3 
3 
5 
44 hours (±4 hours) after completing the balixafortide infusion on Day 3 
 
The plasma concentration of balixafortide will be integrated into the population PK model 
generated using PK data from previous clinical studies. 
 
11. 
EXPLORATORY ASSESSMENTS 
11.1 
Immunogenicity Assessment 
To evaluate immunogenicity and analyze for anti-drug antibodies, blood samples will be 
taken from all patients on the balixafortide + eribulin treatment arm at the visits and timepoints 
shown in Table 14. Sampling for immunogenicity is not required for patients in the eribulin 
monotherapy treatment arm.  
 
Table 14 
Schedule for Immunogenicity Assessments for Patients on the Balixafortide 
+ Eribulin Treatment Arm 
Visit Cycle 
Day 
Timepoint 
1 
1 
Immediately before starting the infusion of balixafortide 
1 
8 
Immediately before starting the infusion of balixafortide 
2 
1 
Immediately before starting the infusion of balixafortide 
2 
8 
Immediately before starting the infusion of balixafortide 
3 
1 
Immediately before starting the infusion of balixafortide 
Every alternate cycle after Cycle 
3 
1 
Immediately before starting the infusion of balixafortide 
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EoT 
- 
Anytime 
EoT: end of treatment 
 
To support the immunogenicity evaluation, corresponding PK samples will also be analyzed 
(Section 10). 
Details on sample collection, processing and shipment to Central Laboratories will be provided 
in a separate laboratory manual. 
11.2 
Exploratory Biomarkers Assessment 
Samples will be tested at laboratories designated by Polyphor. However, all samples will be 
stored at the PPD laboratories facility. PPD laboratories will be responsible for custody of all 
samples during the study and after the study, until their destruction. 
PPD laboratories will manage sample transfer for testing at third party laboratories (when PPD 
is not also responsible for testing). After the testing is completed, samples will be returned to 
PPD for storage. These samples will not be shared with any other party except the laboratories 
that will perform the testing, and the samples and the data from the testing will only be 
available to Polyphor and its delegates, IRB representatives, auditors and inspectors.  
These samples will be stored until a maximum of 5 years after study termination. Samples will 
be destroyed after this period. However, the samples may be destroyed at any time if 
requested by the patient, and in this case no further testing will be done. However, any data 
collected up to the point that the patient requests sample destruction will still be used for future 
analysis as defined in this protocol.  
11.2.1 Tumor Tissue 
All Patients 
For patients who have had a previous tumor biopsy at any time, consent will be required to 
donate this tissue for biomarker assessment. The date of the last tumor biopsy will be 
documented in the patient's source data and eCRF at Screening. If multiple biopsies are 
available, it is recommended to collect a sample of each. 
If such tumor tissue is not available, then the patient will be requested to provide a fresh tumor 
biopsy. If a fresh tumor biopsy is not available, the patient's refusal to provide a tumor biopsy 
or the lack of lesions from which a biopsy can be collected will be documented in the patient's 
source data and eCRF. Patient refusal to provide fresh tumor biopsy or lack of lesions from 
which a biopsy can be collected will not limit a patient's participation in this study. 
Patients at Selected Sites 
Patients can optionally consent to fresh tumor biopsy at Screening and subsequent timepoints 
(Cycle 2 [Day 9; alternatively, for patients in the balixafortide + eribulin treatment arm, biopsy 
can be performed on Day 10 if preferred] and at the EoT Visit) as defined in the Study 
Schedules (Section 1.1). If a biopsy has already been performed within 30 days prior to 
Randomization and tumor tissue is still available, then the fresh tumor biopsy is not required 
during Screening.  
The patient will not be excluded from the study if they do not grant this consent. 
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Any trauma and clinical sequelae related to the mechanics of the tumor biopsy should be 
reported as related to the study procedure. 
Tumor tissues will be analyzed for exploratory biomarkers. CXCR4 expression level, based 
on IHC of archival or fresh biopsy tumor samples, will be assessed and the correlation with 
efficacy parameters will be explored. In addition, tumor-infiltrating lymphocytes, the ratio of 
immune-suppressive and immune response stimulating cells, and expression of immune-
related markers such as granzyme B may be determined by validated standardized 
microscopic procedures. RNA expression of such markers may be measured (e.g. by 
Nanostring technologies). It is recommended that archival formalin-fixed paraffin-embedded 
tumor samples are provided, ideally from the metastatic lesion, however, a very recent biopsy 
can be sent if archival specimen is unavailable. Blocks are preferred, however, if this is not 
possible, then at least 15−20 unstained slides should be prepared for the biomarker analysis. 
Details on sample collection, processing, testing procedures and shipment (if required) to 
Central Laboratories will be provided in a separate laboratory manual. 
11.2.2 Biomarkers in Blood or Plasma 
All Patients 
Blood will be collected from all patients to assess plasma levels of IFN gamma and additional 
cytokine markers at the visits and timepoints shown in Table 15 for patients in the balixafortide 
+ eribulin treatment arm and in Table 16 for patients in the eribulin monotherapy treatment 
arm. 
Table 15 
Schedule for Blood Exploratory Biomarker Assessment of All Patients in the 
Balixafortide + Eribulin Treatment Arm  
Visit Cycle 
Day 
Timepoint 
1 
1 
Immediately before starting the infusion of balixafortide 
1 
1 
Immediately after completing the infusion of balixafortide 
1 
2 
Immediately after completing the balixafortide infusion, but before administration of 
eribulin 
1 
3 
Immediately after completing the infusion of balixafortide 
1 
8 
Immediately before starting the infusion of balixafortide 
1 
9 
Immediately before starting the infusion of balixafortide 
3 
1 
Immediately before starting the infusion of balixafortide 
3 
1 
Immediately after completing the infusion of balixafortide 
3 
2 
Immediately after completing the balixafortide infusion, but before administration of 
eribulin 
3 
3 
Immediately after completing the infusion of balixafortide 
3 
4 
24 hours (±4 hours) after completing the balixafortide infusion on Day 3 only in those 
patients scheduled to have PK sampling at these times (Section 10.1) 
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Visit Cycle 
Day 
Timepoint 
3 
5 
44 hours (±4 hours) after completing the balixafortide infusion on Day 3 only in those 
patients scheduled to have PK sampling at these times (Section 10.1) 
3 
8 
Immediately before starting the infusion of balixafortide 
3 
9 
Immediately before starting the infusion of balixafortide 
PK: pharmacokinetic 
Table 16 
Schedule for Blood Exploratory Biomarker Assessment of All Patients in the 
Eribulin Monotherapy Treatment Arm 
Visit Cycle 
Day 
Timepoint 
1 
2 
Immediately before starting the infusion of eribulin 
1 
9 
Immediately before starting the infusion of eribulin 
3 
2 
Immediately before starting the infusion of eribulin 
3 
9 
Immediately before starting the infusion of eribulin 
 
A re-evaluation of the sampling schedule may take place based on the initial evaluation of 
biomarker levels. 
Patients at Selected Sites 
Additional blood will be collected to assess other exploratory biomarkers from patients at 
selected sites as described in the Study Schedule (Section 1.1). For patients on the 
balixafortide + eribulin treatment arm samples will be taken during: 
• 
Cycle 1 (Days 1, 2, and 8). 
• 
Cycle 2 (Day 9, only in patients who are scheduled to have an optional, fresh tumor 
biopsy; the blood sample can be taken before or after the biopsy). 
• 
Cycle 3 (Days 1 and 2). 
• 
EoT visit. 
 
For patients on the eribulin monotherapy treatment arm samples will be taken during: 
• 
Cycle 1 (Day 2). 
• 
Cycle 2 (Day 9, only in patients who are scheduled to have an optional, fresh tumor 
biopsy; the blood sample can be taken before or after the biopsy). 
• 
Cycle 3 (Day 2). 
• 
EoT visit. 
 
Sampling schedule may change according to the technical requirements of the methods which 
are in place at the selected sites. The blood biomarker analyses may include, but is not limited 
to, enumerating surface marker characterization, RNA expression (e.g. by Nanostring), and 
genomic profiling of circulating tumor cells and cells of the leukocyte fraction (including cells 
participating in immune responses). In addition, receptor occupancy of balixafortide on 
circulating cells by flow cytometric methods may be performed. Further biomarker 
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assessments may include typology and quantification of circulating deoxyribonucleic acid 
(DNA) and miRNA. Blood samples can be treated post collection, ex vivo, with 
immunostimulants to determine the immune competence (e.g. by the True Culture system) 
followed by determination of released factors.  
This study may include additional, optional biomarker components which must be supported 
by an exploratory objective. Such studies are hypothesis generating (e.g. from current and 
future research) and are optional to the patient.   
Details on sample collection, processing and shipment (if required) to Central Laboratories will 
be provided in a separate laboratory manual. 
11.3 
Patient Reported Outcomes 
Patient reported outcomes (PROs) of health-related QoL and health status will be assessed 
using the EORTC-QLQ-C30, FACT-B and EQ-5D instruments. Patients will complete each 
instrument at the Screening Visit and at the EoT visit. Patients on the balixafortide + eribulin 
treatment arm will also complete each instrument pre-dose on Day 1 of each cycle. Patients 
on the eribulin monotherapy treatment arm will also complete each instrument pre-dose on 
Day 2 of each cycle. These instruments should be completed in the same sequence at each 
scheduled assessment. 
During the study treatment phase, patients must complete these instruments in clinic (cannot 
be taken home) and prior to having any clinical assessments, drug dosing, diagnostic testing, 
and to any discussion of their progress with healthcare personnel at the site. Interviewer 
administration in clinic may be used under special circumstances (e.g. patient forgot their 
glasses or feels too ill). 
The EORTC-QLQ-C30 is a validated instrument to measure QoL and assess symptoms and 
side effects of treatment and their impact on everyday life. The instrument is composed of 5 
multi-item functional scales (physical, role, social, emotional and cognitive functioning), a 
global health status/QoL scale, 3 symptom scales (fatigue, nausea/vomiting and pain), and 
6 single items (financial difficulties, appetite loss, diarrhea, constipation, insomnia and 
dyspnea).  
PROs of health-related QoL and health status will be assessed using the FACT-B and EQ-5D 
instruments. The FACT-B and EQ-5D will be given to the patient in the appropriate language.  
The EQ-5D consists of two parts, the EQ-5D descriptive system and the EQ Visual Analogue 
scale (EQ VAS). The descriptive system comprises 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS 
records the patient’s self-rated health visual analogue scale with endpoints labelled ‘the best 
health you can imagine’ and ‘the worst health you can imagine’. 
FACT-B is a self-administered questionnaire designed for patient suffering from BC. It consists 
of 5 subscales (physical wellbeing, social/family wellbeing, emotional wellbeing, functional 
wellbeing, breast subscale) 
This data will be collected via electronic diaries or electronic data capture. Completed 
questionnaires are always considered source document and must be filed accordingly. 
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12. 
STATISTICS 
12.1 
General Statistical Methods 
This section outlines the general study design, study endpoints, and statistical analysis 
strategy for the study. If, after the study has begun, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E9). Changes to exploratory or non-
confirmatory analyses made after the protocol has been finalized, along with an explanation 
as to when and why they occurred, will be listed in the Clinical Study Report (CSR). Post hoc 
exploratory analyses will be clearly identified in the CSR. Full details will be in the Statistical 
Analysis Plan (SAP). Any deviations from the statistical plan will be described and justified in 
a protocol amendment and/or in the CSR. 
All statistical analyses will be carried out using Statistical Analysis System (SAS) version 9.3 
(or later). The SAP will be written and finalized prior to the first patient randomized. The SAP 
will provide a detailed and expanded description of the statistical methods outlined in this 
protocol. Additional analyses, such as in important subgroups, will be described.  
The data from this study will serve a dual purpose:  
(i) To provide efficacy and safety data in the Overall Population, who receive study 
medication as 2nd to 5th line of therapy, for regulatory submissions in the EU and 
jurisdictions in which the 2nd line + eribulin label applies. 
(ii) To provide efficacy and safety data in the 3rd line + population who receive study 
medication as 3rd to 5th line of therapy, for regulatory submissions in the US and 
jurisdictions in which the 3rd line + eribulin label applies. 
 
For the Overall Population, the critical efficacy endpoints shall be PFS and OS. The formal 
analysis of PFS is planned once 346 PFS events have accrued and is expected to be 
conducted when all randomized patients have been followed for a minimum of 12 months. At 
the time of the PFS analysis, an interim analysis of OS will be performed, and a final analysis 
of OS will take place once all randomized patients have been followed for a minimum of 
24 months.  
For the 3rd line + population, the critical efficacy endpoints shall be ORR, PFS, with ORR and 
PFS being co-primary efficacy endpoints. The formal analysis of ORR is planned when all 
such patients have been randomized and followed for a minimum of 6 months. The formal 
analysis of PFS will take place once 286 PFS events have accrued and is expected when all 
randomized patients have been followed for a minimum of 12 months; if the PFS in the 3rd 
line + population meets the allocated alpha level, PFS in the Overall Population will also be 
formally tested at the same alpha level; further, at the time of the PFS analysis an interim 
analysis of OS will be performed. The final analysis of OS will take place once all randomized 
patients have been followed for a minimum of 24 months. 
In this study, the statistical design in the overall, 2nd line + population, with pre-defined alpha 
allocation and recycling, is such that if PFS does not meet statistical significance at its 
allocated alpha level, then the design still allows OS to be tested and, if it meets statistical 
significance at its allocated alpha level, then the study can still be formally positive for efficacy. 
 
Similarly, the statistical design in the overall, 3rd line + population, even if ORR does not meet 
statistical significance at its allocated alpha level then PFS can still be tested and, if it meets 
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statistical significance at its allocated alpha level, the study can still meet its primary objective.  
Further, if PFS does not meet statistical significance at its allocated alpha level, then OS can 
still be tested and, if it meets statistical significance at its allocated alpha level, then the study 
can still be formally positive for efficacy. 
 
Alpha allocation and recycling will ensure control of the overall Type I error rate within each of 
(i) the Overall Population and (ii) 3rd line + population.  
Analyses of biomarkers will be addressed in a separate analysis plan. 
12.2 
Overall Population Efficacy Analysis Plan relevant to the EU and other 
jurisdictions in which the 2nd line + Eribulin Label applies 
12.2.1 Sample Size 
Assuming a median PFS on eribulin of 3.9 months, to test for a hazard ratio versus 
balixafortide + eribulin of 0.699 (corresponding to a median PFS of 5.6 months), a total of 346 
PFS events are required to provide 90% power at the 1-sided 2.0% alpha level. Equally, 346 
PFS events provides 94.6% power for a hazard ratio of 0.674, corresponding to a PFS of 
5.8 months. Assuming a 12-month recruitment period (η=2; Carroll, 2009(3)) and a minimum 
12-month follow-up period after the last patient is randomized, a total of 384 patients will be 
recruited. Patients who discontinue from the study will not be replaced. 
12.2.2 Analysis Sets 
The following analysis sets are defined for the Overall Population:  
• 
Intention-to-treat (ITT) Population is defined as all randomized patients. Efficacy 
data in this population will be summarized by randomized treatment. The co-primary 
endpoint PFS and key secondary efficacy endpoint OS will use the ITT population. 
Patients will be analyzed by the treatment arm to which they are randomized. 
• 
Safety Population is defined as all randomized patients who receive at least one dose 
(or partial dose) of study medication. Patients will be analyzed by the treatment arm 
received, based on the first dose of study drug. 
• 
Response Evaluable Population will be used to evaluate disease response. The 
Response Evaluable Population includes all patients who are randomized in the study 
with measurable disease by RECIST v1.1 (as determined by the Investigator). The co-
primary endpoint analysis of ORR and other secondary endpoint analyses of CBR and 
duration of response will be conducted using the Response Evaluable Population. 
Patients will be analyzed by the treatment arm to which they are randomized. 
• 
Patient Reported Outcome (PRO) Population is defined as all patients in the ITT 
Population where the patient has at least one post randomization PRO value. Patients 
will be analyzed by the treatment arm to which they are randomized. 
12.2.3 Demographics and other Baseline Characteristics 
The following demographic and baseline disease characteristic data for all analysis 
populations will be summarized: age (years), sex, race, ethnicity, ECOG performance status, 
reproductive status, smoking history, height (cm), weight (kg), body surface area (m2), systolic 
BP (mmHg), and diastolic BP (mmHg). Key laboratory parameters will also be summarized. 
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12.2.3.1 Medical History 
Medical history of BC will be summarized for the ITT population. Medical history will include 
time since initial diagnosis (years), time since diagnosis of locally recurrent or metastatic 
disease (years), stage at initial diagnosis, TNM staging, receptor data, receptor status, and 
pathological diagnosis. 
Medical conditions collected at Screening will be mapped by the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) and will be summarized by System Organ Class 
(SOC) and preferred term (PT) for the ITT population. For summary tables, a patient will be 
counted only once per body system and PT.  
Patients will be stratified according to: 
• 
Line of therapy (2nd line versus 3rd line +) for locally recurrent or metastatic BC.  
• 
HR status (positive versus negative) based on ER or PgR status. 
• 
CDK 4/6 inhibitor treatment received previously (received a CDK 4/6 inhibitor 
previously versus not received a CDK 4/6 inhibitor previously). 
• 
Visceral versus non-visceral disease. Visceral metastases will include brain, 
pulmonary, pleural, hepatic and peritoneal involvement (including pleural effusions and 
ascites). Any other sites of metastases (e.g. bone, lymph nodes, and skin) will be 
considered to be non-visceral. Patients with visceral metastases, irrespective of the 
presence of any other metastatic sites (e.g. bone), will be categorized as visceral. All 
other patients without visceral metastases will be categorized as non-visceral. 
12.2.3.2 Medical History of Prior Systemic Cancer/Oncology Therapies 
The number and percent of patients receiving prior anthracycline and/or a taxane will be 
summarized. The number of prior hormonal therapies, cytotoxic chemotherapy regimens for 
BC, neoadjuvant regimens, adjuvant regimens, cytotoxic regimens for locally recurrent, and 
cytotoxic regimens for metastatic disease will be calculated based on prior cancer therapies 
reported on eCRFs and summarized for the ITT population. 
Duration of prior anthracycline and/or taxane use will be summarized descriptively. If a patient 
received multiple treatments of a therapy, the sum of duration will be calculated. 
Prior systemic cancer/oncology therapies will be tabulated for the ITT population using the 
latest version of World Health Organization Drug Dictionary Enhanced (WHO-DDE) and 
Anatomical, Therapeutic, or Chemical (ATC) level 2 classifications and PT.  
12.2.3.3 Previous Radiotherapy and Surgical History 
Previous radiotherapy and surgical history related to BC will be listed for the ITT population. 
Surgical history related to BC and the percentage of patients receiving prior radiotherapy will 
be summarized for the ITT population. 
12.2.4 Patient Disposition 
A summary of patient disposition will display the number of patients who were randomized 
and who comprised each analysis population by treatment arm. In addition, the number of 
patients who discontinued study medication, and the number of patients who discontinued 
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from study, both overall and by reason, will be presented by randomized treatment arm. 
Disposition data, including populations to/from which patients are included/excluded, will be 
presented graphically. 
The three randomization stratification factors, HR status, previous CDK 4/6 inhibitor treatment, 
and visceral disease, will be listed and tabulated as documented on the eCRF and as recorded 
by randomized treatment arm. Any discrepancies between those two sources will be identified 
and summarized. 
12.2.5 Protocol Deviations  
Details on the handling of protocol deviations will be described in a separate Deviations Plan. 
Patients with important protocol deviations will be listed and summarized by treatment arm as 
randomized and for each study site. Important protocol deviations will include, but is not limited 
to, the following: 
• 
Those who entered the study even though they did not satisfy the entry criteria. 
• 
Those who developed withdrawal criteria during the study, but who were not withdrawn 
from the study medication. 
• 
Those who received the wrong study medication or incorrect dose. 
• 
Those who received a concomitant treatment that is prohibited or not recommended. 
These important protocol deviations will be captured by searching relevant data fields reported 
in the clinical database. Final determination of important deviations will be made by the joint 
Polyphor/CRO study team prior to the first planned interim analysis and associated database 
lock. All protocol deviations that are captured will be summarized by category and type and 
will be presented in a data listing. 
12.2.6 Treatments and Medication 
12.2.6.1 Prior and Concomitant Medication 
Prior and concomitant medications will be recorded on the source data and eCRF and coded 
to ATC code and preferred drug name using the latest version of WHO-DDE. Concomitant 
medications will be tabulated for the Safety Population by WHO-DDE ATC. 
12.2.6.2 Subsequent Anti-cancer Therapy 
Subsequent anti-cancer therapy will be summarized for the ITT Population. Subsequent 
anti-cancer therapy will be tabulated using the latest version of WHO-DDE and ATC Level-2 
classifications and PT.  
12.2.6.3 Exposure/Study Medication 
Overall exposure to study medications, and study medication administration for each cycle 
and all cycles combined will be summarized for the Safety Population. Overall exposure to 
study medication will be summarized in terms of exposure duration and cumulative number of 
cycles. 
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12.2.7 Efficacy Analyses 
12.2.7.1 Primary Endpoint: Progression Free Survival 
PFS time (defined as the time from randomization to the first progression or death, as judged 
by an IRC) is the primary endpoint. The alpha allocation will be 0.040 2-sided. PFS will be 
analyzed via Cox regression modelling in the ITT population. Patients free from progression 
and death will be censored at their last follow-up visit. The analysis will be stratified for 
randomization stratification factors and a fixed effect term will be included for randomized 
treatment. The hazard ratio will be estimated from the model along with the associated 96% 
confidence interval (CI) and 2-sided p-value. The data will also be displayed using Kaplan-
Meier curves and median PFS times will be estimated. 
Supportive analyses for PFS will be conducted using: 
(i) A stratified log rank test on PFS as determined by IRC; strata will be the randomization 
stratification factors. The 2-sided p-value will be extracted and presented alongside the 
results of the Cox analysis; and  
(ii) Cox regression analysis on PFS as determined by the local Investigator's review. 
 
12.2.7.2 Key Secondary Endpoint: Overall survival 
OS will be analyzed using the same Cox model as for PFS. The CI coverage for OS at the 
planned interim and at the final analysis will be determined by the allocated alpha level. A 
sensitivity analysis using a stratified log rank test will be performed, again as per the analysis 
of PFS. 
The OS proportion at 6, 12 and 18 months, including 95% CIs, will also be presented. 
12.2.7.3 Type I Error Control 
The formal analysis of PFS is planned for the Overall Population once 346 PFS events have 
accrued and is expected when all randomized patients have been followed for a minimum of 
12 months. An interim analysis of OS will take place at the same time, and the final analysis 
of OS will take place once all randomized patients have been followed for a further 12 months 
(i.e. a minimum of 24 months). 
The overall Type I error rate will be controlled at 5% across the primary and key secondary 
endpoint analyses by means of alpha allocation and recycling as described in Figure 2. 
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Figure 2 
Type I Error Control for Primary and Secondary Efficacy Analyses in the 
Overall Population 
 
OS: overall survival; PFS: progression free survival. 
 
12.2.7.4 Other Secondary Endpoints 
Analysis of the other secondary endpoints in the overall, 2nd line + population, i.e. ORR, CBR, 
DCR, time to response, and duration of response will not be subject to Type I error control. 
Statistical tests will be 2-sided with a nominal Type I error rate of 0.05. 
ORR will be analyzed by exact logistic regression and be stratified for randomization 
stratification factors. The odds ratio will be estimated from the model along with the associated 
95% CI and 2-sided p-value. Exact Clopper-Pearson 2-sided 95% CI limits will be calculated 
for the proportion of patients with ORR in each arm. 
ORR analyses will be performed for the Response Evaluable Population. Patients who do not 
have measurable disease at baseline will be excluded from the population. In addition to 
presenting ORR, the best response using response categories CR, PR, SD, PD, and not 
evaluable (NE) will be tabulated. The proportion of the response in each response category 
will be calculated. Patients who do not have any post-baseline tumor assessment will be 
counted under the category NE. SD requires at least one post-baseline scan performed at 
6 weeks (42 days) or later. Patients who did not have any post baseline scans for the 6 week 
assessment or later, and who also do not have a documented PD will be counted as NE. 
Duration of response will be analyzed in the Response Evaluable Population, and CBR will be 
analyzed in both the Response Evaluable Population and ITT population. 
CBR will be compared between the treatment arms using exact logistic regression as 
described for ORR. Exact Clopper Pearson 2-sided 95% confidence limits will be calculated 
for the CBR of each treatment arm. 
Duration of response will be analyzed via Cox regression modelling with a fixed effect term for 
randomized treatment. The hazard ratio will be estimated from the model along with the 
associated 95% CI and 2-sided p-value. The data will also be displayed using Kaplan-Meier 
curves; median duration of response and the 95% CIs will be estimated from the Kaplan-Meier 
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by treatment arm. A supportive analysis will be performed based on the expected duration of 
response as per Ellis et al (2008) (59). 
12.2.7.5 Exploratory Efficacy Endpoints 
Analysis of exploratory efficacy endpoints will not be subject to Type I error control. Statistical 
tests will be 2-sided with a nominal type I error rate of 0.05. 
EORTC-QLQ-C30-QoL: As per the user's manual, raw scores for the EORTC-QLQ-C30 will 
be transformed using a linear transformation to standardize the results so that scores range 
from 0 to 100. At each assessment point, summary statistics of absolute scores and changes 
from baseline will be calculated by treatment group for each scale for both the raw score and 
the linear transformed score. Scores will be compared between treatments over time using 
mixed model repeated measures.  
EQ-5D: The EQ-5D data will be scored and handled as recommended in its user’s manual, 
and analyzed in a similar way to the EORTC-QLQ-C30.  
FACT-B: The FACT-B data will be scored and handled as recommended in its user’s manual, 
including handling of missing data both within the subscales and overall. The scores will be 
summarized by randomized treatment group at each assessment point. The scores will also 
be analyzed over time using mixed model repeated measures analysis in a similar way to the 
EORTC-QLQ-C30 and EQ-5D. 
The analysis of the EORTC-QLQ-C30, EQ-5D and FACT-B will be performed in the PRO 
Population. 
Relationship between biomarkers and clinical outcome: The relationship between 
baseline biomarkers (including ER status, PgR status, CXCR4 expression levels, cytokines 
[e.g. IFN-gamma], immune cells profile and RNA expression) and ORR, PFS and OS will be 
explored using a variety of exploratory data analysis methods including Cox and logistic 
regression models, time dependent covariate analysis (for biomarker measured longitudinally) 
and multivariate stepwise model selection methods. All such analyses will be essentially 
descriptive and hypothesis generating in nature.  
12.3 
3rd line + Population Efficacy Analysis Plan relevant to the US and other 
jurisdictions in which the 3rd line + Eribulin Label applies 
12.3.1 Sample Size 
Assuming a median PFS on eribulin of 3.9 months, to test for a hazard ratio versus 
balixafortide + eribulin of 0.674 (corresponding to a median PFS of 5.8 months), a total of 286 
PFS events are required to provide 90% power at the 1-sided 2.0% alpha level. Assuming a 
12-month, non-linear recruitment period (η=2; Carroll, 2009(3)) and a minimum 12-month 
follow-up period after the last patient is randomized, a total of 320 3rd line + patients will be 
recruited.  
12.3.2 Analyses Sets 
12.3.2.1 3rd line + Population 
The following analysis sets are defined for the 3rd line + population:  
• 
ITT Population (3rd line +) is defined as all randomized patients in the 3rd line + 
population. Efficacy data in this population will be summarized by randomized 
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treatment. The co-primary endpoint PFS and key secondary efficacy endpoint OS will 
use the ITT population. Patients will be analyzed by the treatment arm to which they 
are randomized. 
• 
Response Evaluable Population (3rd line +) will be used to evaluate disease 
response. The Response Evaluable Population includes all patients in the 3rd line + 
population who are randomized in the study with measurable disease by RECIST v1.1 
(as determined by the Investigator). The co-primary endpoint analysis of ORR and 
other secondary endpoint analyses of CBR and duration of response will be conducted 
using the Response Evaluable Population. Patients will be analyzed by the treatment 
arm to which they are randomized. 
• 
PRO Population (3rd line +) is defined as all patients in the 3rd line + population where 
the patient has at least one post randomization PRO value. Patients will be analyzed 
by the treatment arm to which they are randomized. 
• 
Safety Population is the same as that defined for the overall, 2nd line + population.  
 
12.3.3 Demographics and Other Baseline Characteristics 
Will be summarized in the 3rd line+ population in the same fashion as for the overall, 2nd line + 
population. 
12.3.3.1 Medical History 
Will be summarized in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population. 
12.3.3.2 Medical History of Prior Systemic Cancer/Oncology Therapies 
Will be summarized in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population. 
12.3.3.3 Previous Radiotherapy and Surgical History 
Will be summarized in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population. 
12.3.4 Patient disposition 
Will be summarized in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population. 
12.3.5 Protocol Deviations 
Will be handled in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population. 
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12.3.6 Treatments and Medication 
12.3.6.1 Prior and Concomitant Medication 
Will be summarized in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population. 
12.3.6.2 Subsequent Anti-cancer Therapy  
Will be summarized in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population.  
12.3.6.3 Exposure/Study Medication 
Will be summarized in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population. 
12.3.7 Efficacy Analyses 
12.3.7.1 Co-Primary Endpoints: Objective Response Rate and Progression Free 
Survival 
Objective Response Rate 
Will be analyzed in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population. The alpha allocation will be 0.001 2-sided. 
 
 
Progression Free Survival 
Will be analyzed in the 3rd line+ population in the same fashion as for the overall, 2nd line + 
population. The alpha allocation will be 0.040 2-sided. If PFS in the 3rd line + population is met 
at the allocated alpha level, PFS in the overall population will also be formally tested at the 
same alpha level. 
12.3.7.2 Key Secondary Endpoint: Overall survival 
Will be analyzed in the 3rd line + population in the same fashion as for the overall, 2nd line + 
population. The alpha allocation will be between 0.001 and 0.002 2-sided at the interim and 
between 0.008 and 0.050 at the final analysis depending on the results of previous analyses. 
12.3.7.3 Type I Error Control 
The formal analysis of ORR is planned for the 3rd line + population once all such patients have 
been randomized and followed for a minimum of 6 months. The formal analysis of PFS will 
take place once 286 PFS events have accrued and is expected when all randomized patients 
have been followed for a minimum of 12 months; if the PFS in the 3rd line + population meets 
the allocated alpha level, PFS in the Overall Population will also be formally tested at the same 
alpha level. At the time of the PFS analysis, an interim analysis of OS will be performed and 
the final analysis of OS will take place once all randomized patients have been followed for a 
minimum of 24 months at which time 226 OS events are expected.  The overall Type I error 
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rate will be controlled at 5% across the primary and secondary endpoints by means of alpha 
allocation and recycling as described in Figure 3. 
 
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Figure 3 Type I Error Control for Primary and Secondary Efficacy Analyses in the 3rd line + (3rd to 5th line of therapy) 
Population 
 
 
ORR: objective response rate; OS: overall survival; PFS: progression free survival; Popln: population. 
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12.3.7.4 Other Secondary Endpoints 
Analysis of the other secondary endpoints of CBR, DCR, time to response, and duration of 
response will not be subject to Type I error control. Statistical tests will be 2-sided with a 
nominal Type I error rate of 0.05.  These endpoints will be analyzed in the 3rd line + population 
in the same fashion as for the overall, 2nd line + population.  
12.3.7.5 Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints EORTC-QLQ-C30, EQ-5D, FACT-B and the relationship 
between baseline biomarkers and efficacy outcomes will be analyzed in the 3rd line + 
population in the same manner as described for the overall, 2nd line + population.  Analysis of 
the other exploratory efficacy endpoints will not be subject to Type I error control. Statistical 
tests will be 2-sided with a nominal type I error rate of 0.05.  
12.4 
Safety Analysis 
The Safety Population is defined as all patients who received at least 1 dose (or partial dose) 
of study medication regardless of line of prior therapy. Summaries of AEs and other safety 
parameters will be provided by treatment arm received, based on the first dose of study drug. 
12.4.1 Adverse Events 
AEs will be classified using the latest version of MedDRA classification system. The severity 
will be graded according to the NCI CTCAE v5.0 whenever possible. All AEs reported from 
the first dose of study drug until 30 days (+7 days) after the last dose of study drug will be 
considered as TEAEs and will be summarized descriptively by treatment, and by the frequency 
of patients experiencing TEAEs corresponding to body systems and MedDRA PT. Patients 
with multiple occurrences of events will only be counted once at the maximum severity/grade 
to study drug for each PT, SOC, and overall.  
All AEs will be summarized by relatedness to study medication and may be summarized by 
cycle as warranted. Detailed information collected for each AE will include a description of the 
event, duration, whether the AE was serious, severity, relationship to study drug, action taken, 
and clinical outcome. AEs that are reported as possibly, probably, or definitely related to study 
drug will be counted as related to study drug. AEs with a missing relationship will be 
considered as “related” for this summary. 
Any AEs leading to death or discontinuation of study medication, events classified as NCI 
CTCAE v5.0 Grade 3 or higher, AESIs (see Section 9.1), study drug-related events, and SAEs 
will be monitored with special attention. 
The format and content of summary tables and individual patient listings is described in the 
SAP.  
12.4.2 Laboratory Results 
Hematology and chemistry laboratory data will be summarized by treatment and by cycle. The 
laboratory results will be graded according to the NCI CTCAE v5.0 severity grade. The 
frequencies of the worst severity grade observed will be displayed by study medication. Shift 
tables will be provided to examine the distribution of laboratory toxicities. For parameters for 
which an NCI CTCAE v5.0 scale does not exist, the frequency of patients with values below, 
within, and above the normal ranges will be summarized by treatment. 
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12.4.3 Analysis of Vital Signs 
Each vital sign (temperature, BP [systolic and diastolic], respiration rate, and heart rate) and 
respective change from baseline will be summarized and presented by treatment arm and 
study visit. Patients with clinically significant abnormalities in vital signs as compared to 
baseline will be listed. 
12.4.4 Physical Examination 
A summary table for the shift from baseline to post-baseline timepoints for physical 
examination will be provided for the Safety population. All physical examination results will be 
presented in a data listing. 
12.4.5 12-Lead Electrocardiogram 
ECG data will be summarized by study medication arm and by cycle using descriptive statistics 
for change-from-baseline values and categorical outliers. Any clinically significant changes will 
be recorded as AEs. 
QTc intervals between >480 msec and ≤500 msec (Grade 2) and or between ≥501 msec from 
baseline (Grade 3) will be identified and summarized by study medication arm. 
12.4.6 Exposure During Pregnancy 
Patients who become, or are found to be, pregnant during exposure to study medication, will 
be summarized by treatment arm. The outcome of the pregnancy will be summarized in 
accordance with the Pregnancy Reporting Form including termination, still birth and live birth. 
In the event of a termination, the reasons for termination will be summarized and the structural 
integrity of the terminated fetus will also be summarized where possible. For live birth, the 
presence of any congenital anomalies will be summarized.   
12.5 
Deviations from the Original Statistical Plan 
Any deviations from the original statistical plan as described in this Protocol will be agreed by 
the Sponsor and documented and justified in a Protocol Amendment, the final SAP or the 
clinical trial report, as appropriate. 
12.6 
Data Management 
An eCRF and trial database will be created to capture and store trial data. All trial data will be 
processed and stored in a secure database. 
The Investigator, or designee, will be responsible for entering data directly into the trial 
database via a secure internet connection, according to instructions provided for data entry. 
During data entry, range checks, plausibility checks, and consistency checks will be performed 
to ensure accuracy and completeness of the data being collected. Data queries will also be 
generated and resolved according to the pre-prepared data management plan. At 
pre-determined time points, SAS datasets will be generated from the trial database ready for 
analysis. A complete audit trail of all corrections will be available for inspection. 
When data have been entered, reviewed and edited, the Investigator will be notified to review 
and sign the eCRF electronically as per the agreed project process, data will be locked to 
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prevent further editing, and a copy of the eCRF and data query sheets will be archived at the 
Investigator’s site. 
12.7 
Data Safety Monitoring Committee 
An independent DSMC will be established with the responsibility of safeguarding the safety of 
study participants by ongoing review of accumulating safety data during the conduct of this 
open label study. The DSMC will provide ongoing review of study conduct and patient 
management and make appropriate recommendations to the Sponsor based on the reported 
data. The final responsibility for acting upon DSMC recommendations lies with the Sponsor. 
The DSMC will be operational prior to enrolment of the first subject into the study. The 
composition and operation of the DSMC is described in the DSMC charter. The DSMC will 
also provide oversight and governance of the planned interim analyses of ORR and OS. 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The clinical monitor(s) should be given direct access to primary patient data (i.e., source data) 
which supports the data on the eCRFs for the study, i.e., hospital notes, appointment books, 
original laboratory records, etc. Because this enters the realm of patient confidentiality, this 
fact must be included in the ICF that the patient signs. Other authorized persons such as 
auditors and inspectors from regulatory authorities may need to have direct access to this 
source data. 
13.1 
Source Data 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the study. Source data are contained in source documents 
(original records or certified copies).  
All key data must be recorded in the patient’s medical records. 
13.2 
Source Documents 
Source documents are defined as original documents, data and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, any patient diaries or evaluation check 
lists, pharmacy dispensing records, recorded data from automated instruments, copies or 
manuscripts certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, X-rays, patient files, records kept at the pharmacy, at 
the laboratories and at medico technical departments involved in the clinical trial).  
13.3 
Direct Access 
Direct access is defined as the permission to examine, analyze, verify and reproduce any 
records and reports that are important to evaluation of a clinical trial. Any party (e.g. Regulatory 
Authorities, Polyphor Ltd, or CRO monitors and auditors) with direct access should take all 
reasonable precautions within the constraints of the applicable regulatory requirements to 
maintain the confidentiality of patient identities and Polyphor Ltd proprietary information. 
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14. 
QUALITY CONTROL AND QUALITY ASSURANCE  
An independent audit at the study site may take place at any time during or after the study. 
The independent audit can be carried by the Quality Assurance (QA) department of Polyphor 
Ltd, or the QA department of a CRO. In addition, an inspection may be carried out by a 
regulatory authority.  
14.1 
Quality Control 
Quality Control is defined as the operational techniques and activities undertaken within the 
QA system to verify that the requirements for quality of the study related activities have been 
fulfilled. 
Quality Control should be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. 
14.2 
Quality Assurance 
QA is defined as the planned and systematic actions that are established to ensure that the 
study is performed, and the data are generated, documented (recorded) and reported in 
compliance with GCP and the applicable regulatory requirements. 
14.2.1 Inspection 
An Inspection is defined as the act by a Regulatory Authority of conducting an official review 
of documents, facilities, records and any other resources that are deemed by the authorities 
to be related to the clinical trial and that may be located at the site of the study, or at Polyphor 
Ltd's facilities or at any other establishments deemed appropriate by the Regulatory 
Authorities. 
14.2.2 Audit 
An Audit is a systematic and independent review of study-related activities and documents to 
determine whether the validated study-related activities will be conducted, and the data will 
be recorded, analyzed and accurately reported according to the Protocol, designated SOPs, 
GCP and the applicable regulatory requirements.  
15. 
ETHICS 
This clinical trial will be conducted in compliance with this Protocol, the GCP guidelines of ICH, 
EU Directive 2001/20/EC, and Commission Directive 2005/28/EC, and EC ENTR/CT2, the 
guidelines of the World Medical Association Declaration of Helsinki in its revised edition 
(Fortaleza, Brazil, 2013), the General Data Protection Regulation (EU) 2016/679, designated 
SOPs, and with local laws and regulations relevant to the use of new therapeutic agents in the 
country of conduct. 
The IECs and IRBs must be constituted according to the local laws/guidelines. 
15.1 
Independent Ethics Committee/Institutional Review Board Approval 
Polyphor Ltd will be responsible for preparing and submitting the regulatory approval in each 
country in which the study is to be conducted. In addition, Polyphor Ltd will be responsible for 
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informing the Regulatory Authorities of relevant changes to the Protocol. Approval must be 
received from the Regulatory Authority in each country prior to release of study drugs and 
patient recruitment.  
Before initiating a study, the Investigator should have received written and dated 
approval/favorable opinion from the relevant IECs/IRBs for the Protocol (and any 
amendments), written ICF, consent form updates, patient recruitment procedures (e.g. 
advertisements), and any other written information to be provided to patients. Approval will be 
indicated in writing with reference to the final Protocol number and date. Details of the 
IECs/IRB's constitution including names of its members and what function they perform on the 
committee (e.g. chairman, specialist, lay-member) should be made available to Polyphor Ltd 
During the study, the Investigator should provide all documents that are subject to review to 
the IECs/IRBs. 
Each participating center will submit the Protocol to the local hospital/university/independent 
IEC/IRB, and their written unconditional approval obtained and submitted to Polyphor Ltd 
before the start of the study. Those with potential conflicts of interest (e.g. Investigators of this 
study, Polyphor board members) should not partake in the IEC/IRB decision process. 
Polyphor Ltd will ensure an up-to-date Investigator’s Brochure is available and will supply the 
Investigator with the Investigator’s Brochure and Protocol for the Investigator to submit to the 
IECs/IRB for the Protocol’s review and approval. Verification of the IECs/IRB unconditional 
approval of the Protocol will be transmitted to Polyphor Ltd prior to the start of the study. This 
approval must refer to the study by exact Protocol title and number, identify the documents 
reviewed and state the date of review. 
The IEC/IRB must be informed by the Investigator of all subsequent Protocol amendments 
and of unexpected SAEs occurring during the study, which are likely to affect the safety of the 
patients or the conduct of the study.  
The Investigator should provide the IEC/IRB with all relevant amendments or updates of the 
Protocol and Investigator’s Brochure. Also, the Investigator should provide written reports to 
the IEC/IRB annually or more frequently if requested on any change significantly affecting the 
conduct of the study and/or increasing risk to the patients. A final report of study outcome, if 
required, should also be submitted by the Investigator to the IEC/IRB. 
15.2 
Informed Consent 
Before beginning any study procedure on a patient, it is the responsibility of the Investigator 
to obtain voluntary written Informed Consent from all patients or their legal representatives. 
The principles of Informed Consent in the Declaration of Helsinki should be implemented in 
this clinical trial before any Protocol specified procedures are carried out. Information should 
be given in both oral and written form whenever possible and deemed appropriate by the 
IEC/IRB. The information must be expressed in a way that can be comprehended by lay 
people. Patients, their relatives, or if necessary, their legal representatives must be given 
ample opportunity to enquire about details of the study. 
The Investigator will explain the nature, purpose and risks of the study and provide the patient 
or his/her legal representative with a copy of the study information sheet. The patient or his/her 
legal representative will be given sufficient time to consider the study's implications before 
deciding whether to participate. The Investigator must notify the patient or his/her legal 
representative about the option to withdraw consent at any time. 
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Consent forms must be in a language fully comprehensible to the prospective patient or his/her 
legal representative. Informed Consent will be documented by using a written ICF approved 
by the IEC/IRB and signed by the patient or his/her legal representative, and the Investigator 
obtaining the consent. The ICF will also be annotated with the study patient number. 
The written Informed Consent document will comply with ICH guidelines, embody the 
elements of Informed Consent as described in the Declaration of Helsinki and will also comply 
with local regulations. Consent must be documented by the patient’s (or his/her legal 
representative's) dated signature. The signature confirms the Consent is based on information 
that has been understood. Each patient’s signed ICF must be kept on file by the Investigator 
for possible inspection by Regulatory Authorities and Polyphor Ltd  
The patient or his/her legal representative will be given an original hardcopy of the signed ICF. 
Should there be any amendments to the final Protocol that would directly affect the patient’s 
participation in the study (e.g. a change in any procedure), the ICF must be amended to 
incorporate this modification and the patients or their legal representatives must agree to sign 
this amended ICF indicating that they re-consent to participate in the study. 
15.3 
Modification of Protocol 
The Investigator(s) must adhere to this Protocol and will be responsible for enrolling only those 
patients who have met the eligibility criteria. The Investigator(s) will be required to sign an 
Investigator Agreement to confirm acceptance and willingness to comply with the Protocol. 
The Investigator must not implement any deviation from, or changes of, the Protocol without 
agreement by Polyphor Ltd, and prior review and documented approval/favorable opinion from 
the IEC/IRB of an amendment. The only exceptions are where it is necessary to eliminate an 
immediate hazard(s) to study patients, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g. change in monitor[s], change of telephone number[s]). 
As soon as possible, the implemented deviation or change, the reasons for it, and, if 
appropriate, the proposed Protocol amendment(s) should be submitted: 
• 
To the IEC/IRB for review and approval/favorable opinion 
• 
To the Regulatory Authority(ies) according to local laws/guidelines. 
The party initiating an amendment must confirm it clearly in writing and it must be signed and 
dated by Polyphor Ltd and the Principal Investigator. Polyphor Ltd (or its designated CRO) will 
ensure that the Investigators submit necessary Protocol amendments to the appropriate 
IEC/IRB. 
All agreed Protocol amendments must be clearly documented using standard procedures as 
defined by Polyphor Ltd, and must be signed and dated by Polyphor Ltd, and the Investigator.  
15.4 
Safety Reporting 
The Sponsor and its authorized designees are responsible for clinical trial and safety reporting 
to Regulatory Authorities and ethics committees in each country in which the study is 
conducted (see Section 9.2.5.3). 
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15.5 
Trial Termination 
Polyphor Ltd reserves the right to terminate the study at any time. Study termination may also 
be requested by a competent authority/ies. 
15.6 
End of Trial Notification and Submission of Summary Report 
Polyphor Ltd is responsible for preparing and submitting the end of trial notification to the 
Ethics Committees and Regulatory Authorities in the EU Member States in which the study 
has been conducted. This must be submitted within 90 days of the end of the trial (15 days if 
the trial is terminated early). Notification of the end of trial will be provided to the FDA in the 
Annual Report. 
For this purpose, the end of the trial (trial completion) is defined in Section 7.10. Any change 
to this definition is considered a significant amendment and MUST be notified to (and approval 
sought from) the Ethics Committees and the Regulatory Authorities concerned. 
Polyphor Ltd will be responsible for preparing and submitting a summary of the CSR to the 
Regulatory Authorities in each country in which the study was conducted within 12 months of 
the end of the study.  
Polyphor Ltd will be responsible for uploading the End of Trial summary results to the 
European Clinical Trials Database (EudraCT) as per the current European legislation. 
Polyphor Ltd will also report the end of trial information in the US clinical trial register.  
16. 
DATA HANDLING AND RECORD KEEPING  
16.1 
Completion of Electronic Case Report Forms 
Data will be collected and recorded in an eCRF. Data entered in the eCRF are stored in a 
centralized database on a remote server. Data will be entered directly into the eCRF via a 
single data entry process. The data entry activities are regulated and described in the eCRF 
manual. 
Data reported on the eCRF that are derived from source documents must be consistent with 
the source documents or the discrepancies should be explained. 
16.2 
Confidentiality 
In order to maintain patient confidentiality, only a site number and an anonymized patient 
number will identify all study patients on eCRFs and other documentation submitted to the 
Sponsor. Additional patient confidentiality issues (if applicable) are covered in the Clinical Trial 
Agreement. 
Data collected during this study may be used to support the development, registration or 
marketing of balixafortide. Polyphor Ltd will control all data collected during the study and will 
abide by the General Data Protection Regulation (EU) 2016/679 concerning the processing 
and use of patients’ personal data. For the purpose of data privacy legislation, Polyphor Ltd 
will be the data controller. 
After patients have consented to take part in the study their medical records and the data 
collected during the study will be reviewed by the Sponsor. These records and data may, in 
addition, be reviewed by the following: independent auditors who verify the data on behalf of 
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Polyphor Ltd; third parties with whom Polyphor Ltd may develop, register or market 
balixafortide; national or local regulatory authorities and the IRB/IECs that gave approval for 
this study to proceed. 
All US-based investigational sites and laboratories or entities providing support for this trial, 
must, where applicable, comply with the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996. An investigational site that is not a Covered Entity as defined by HIPAA, 
must provide documentation of this fact to Polyphor Ltd. 
The results of this study may be recorded and transferred to and used in other countries 
throughout the world, which may not afford the same level of protection that applies within the 
EU. The purpose of any such transfer would be to support regulatory submissions in other 
countries. 
16.3 
Archiving and Retention of Investigational Records 
All 'essential documents' (as described in the ICH GCP Guidelines) must be retained by 
Polyphor Ltd and the Investigator for at least 15 years after the completion of the clinical trial. 
These documents may be retained for a longer period, however, if required by the applicable 
regulatory requirements (e.g. ICH GCP) or by an agreement with Polyphor Ltd. It is the 
responsibility of the Sponsor to inform the Investigator as to when these documents no longer 
need to be retained. The Investigator must obtain written permission from Polyphor Ltd prior 
to the destruction of any study document. 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained. Databases are backed up by the database administrator in conjunction with any 
updates or changes to the database. 
At critical junctures of the protocol (e.g., production of interim and final reports), data for 
analysis is locked and cleaned per established procedures.  
To enable evaluations and/or audits from Regulatory Authorities or the Sponsor, the 
Investigator agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed ICFs, copies 
of all CRFs, safety reporting forms, source documents, and detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, telephone calls reports). The records should be retained by the Investigator 
according to ICH, local regulations, or as specified in the Clinical Trial Agreement, whichever 
is longer, but at a minimum, all study documentation must be retained for 2 years after the last 
marketing application approval in an ICH region or after at least 2 years have elapsed since 
formal discontinuation of clinical development. 
If the Investigator becomes unable, for any reason, to continue to retain study records for the 
required period (e.g. retirement, relocation), the Sponsor should be prospectively notified. 
The study records must be transferred to a designee acceptable to the Sponsor, such as 
another Investigator, another institution. The Investigator must obtain the Sponsor’s written 
permission before disposing of any records, even if retention requirements have been met. 
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17. 
FINANCING AND INSURANCE 
The costs necessary to perform the study will be agreed with the Investigator and will be 
documented in a separate financial agreement that will be signed by the Investigator, Sponsor, 
and other relevant parties as applicable, in advance of the study commencing.  
Polyphor Ltd has insurance coverage for study-related medicine-induced injury and other 
liabilities incurred during clinical studies which will provide compensation for any trial related 
injury according to local laws and regulations. 
18. 
PUBLICATION POLICY 
Publication of study results is discussed in the Clinical Trial Agreement. 
It is intended that the results of the study may be published as scientific literature. Results may 
also be used in submissions to Regulatory Authorities. The following conditions are to protect 
commercial confidential materials (patents, etc.), not to restrict publication. 
All information concerning balixafortide (such as patent applications, formulae, manufacturing 
processes, basic scientific data, or formulation information supplied to the Investigator by 
Polyphor Ltd and not previously published) is considered confidential by Polyphor Ltd and 
shall remain the sole property of Polyphor Ltd. The Investigator agrees not to use it for other 
purposes without Polyphor Ltd’s written consent. 
It is understood by the Investigator that Polyphor Ltd will use the information developed in this 
clinical trial in connection with the development of balixafortide and therefore may be disclosed 
as required to Polyphor Ltd’s Investigators or any appropriate international Regulatory 
Authorities. In order to allow for the use of information derived from this clinical trial, the 
Investigator understands that he/she has an obligation to provide Polyphor Ltd with complete 
test results and all data developed during this study. 
Prior to submitting the results of this study for publication or presentation, the Investigator will 
allow Polyphor Ltd 30 days in which to review and comment upon the publication manuscript. 
Polyphor Ltd agrees that before it publishes any results of this study, it shall provide the 
Investigators at least 30 days for full review of the publication manuscript. In accordance with 
generally recognized principles of scientific collaboration, co-authorship with any Polyphor Ltd 
personnel will be discussed and mutually agreed upon before submission of a manuscript to 
a publisher. 
All manuscripts, abstracts or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by Polyphor Ltd in advance of submission. The 
review is aimed at protecting Polyphor Ltd proprietary information existing either at the date of 
the commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data shall be set out in the agreement 
between each Investigator and Polyphor Ltd.  
 
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19. 
REFERENCES 
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18. 
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Xu TP, Shen H, Liu LX, Shu YQ. The impact of chemokine receptor CXCR4 on breast 
cancer prognosis: a meta-analysis. Cancer Epidemiol. 2013;37(5):725-31. 
22. 
Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin 
monotherapy versus treatment of physician's choice in patients with metastatic breast 
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study. 
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Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, et al. Phase III 
open-label randomized study of eribulin mesylate versus capecitabine in patients with 
locally advanced or metastatic breast cancer previously treated with an anthracycline 
and a taxane. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2015;33(6):594-601. 
24. 
Pivot X, Marmé F, Koenigsberg R, Guo M, Berrak E, Wolfer A. Pooled analyses of 
eribulin in metastatic breast cancer patients with at least one prior chemotherapy. 
Annals of Oncology. 2016;27(8):1525-31. 
25. 
Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 
2010;16(11):2927-31. 
26. 
Ali S, Lazennec G. Chemokines: novel targets for breast cancer metastasis. Cancer 
Metastasis Rev. 2007;26(3-4):401-20. 
27. 
Galsky MD, Vogelzang NJ, Conkling P, Raddad E, Polzer J, Roberson S, et al. A phase 
I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer. 
Clin Cancer Res. 2014;20(13):3581-8. 
28. 
Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of 
chemokine receptors in breast cancer metastasis. Nature. 2001;410(6824):50-6. 
29. 
Xu C, Zhao H, Chen H, Yao Q. CXCR4 in breast cancer: oncogenic role and 
therapeutic targeting. Drug design, development and therapy. 2015;9:4953-64. 
30. 
Liang Z, Wu T, Lou H, Yu X, Taichman RS, Lau SK, et al. Inhibition of breast cancer 
metastasis by selective synthetic polypeptide against CXCR4. Cancer Res. 
2004;64:4302-8. 
31. 
Hiller D, Chu QD. CXCR4 and axillary lymph nodes: review of a potential biomarker for 
breast cancer metastasis. Int J Breast Cancer. 2011;2011:420981. 
32. 
Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing 
carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in 
pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212-7. 
33. 
Andtbacka RHI, Yushak M, Ross M, Grossmann K, Pierce R, Tsiroyannis E, et al. X4P-
001, an Orally Bioavailable CXCR4 Antagonist, Increases T Cell Infiltration in Human 
Metastatic Melanoma.  Poster presented at The Society for Immunotherapy of Cancer 
Annual Meeting , November 8–12, 2017 ·; National Harbor, Maryland2017. 
34. 
Xiang J, Hurchla MA, Fontana F, Su X, Amend SR, Esser AK, et al. CXCR4 Protein 
Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances 
Chemotherapy Effect in Triple-Negative Breast Cancer. Mol Cancer Ther. 
2015;14(11):2473-85. 
35. 
Sison EA, Magoon D, Li L, Annesley CE, Romagnoli B, Douglas GJ, et al. POL5551, 
a novel and potent CXCR4 antagonist, enhances sensitivity to chemotherapy in 
pediatric ALL. Oncotarget. 2015;6(31):30902-18. 
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36. 
Barone A, Sengupta R, Warrington NM, Smith E, Wen PY, Brekken RA, et al. 
Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and 
synergistically improves survival in an intracranial mouse model of glioblastoma. 
Oncotarget. 2014;5(20):9811-22. 
37. 
Gagner JP, Sarfraz Y, Ortenzi V, Alotaibi FM, Chiriboga LA, Tayyib AT, et al. 
Multifaceted C-X-C Chemokine Receptor 4 (CXCR4) Inhibition Interferes with Anti-
Vascular Endothelial Growth Factor Therapy-Induced Glioma Dissemination. Am J 
Pathol. 2017;187(9):2080-94. 
38. 
Karpova D, Bräuninger S, Wiercinska E, Krämer A, Stock B, Graff J, et al. Mobilization 
of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) 
in healthy volunteers-results of a dose escalation trial. J Transl Med. 
2017;15(2):DOI:10.1186/s12967-016-1107-2. 
39. 
Cortes J, Vahdat L, Blum JL, Twelves C, Campone M, Roche H, et al. Phase II study 
of the halichondrin B analog eribulin mesylate in patients with locally advanced or 
metastatic breast cancer previously treated with an anthracycline, a taxane, and 
capecitabine. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2010;28(25):3922-8. 
40. 
Vahdat LT, Pruitt B, Fabian CJ, Rivera RR, Smith DA, Tan-Chiu E, et al. Phase II study 
of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer 
previously treated with an anthracycline and a taxane. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 2009;27(18):2954-61. 
41. 
Pernas S, Martin M, Kaufman PA, et al. Balixafortide plus eribulin in HER2-negative 
metastatic breast cancer: a phase I, single-arm, dose-escalation trial. Lancet Oncol. 
2018;19(6):812-24. 
42. 
Eisai. HALAVEN(R) (Eribilun) SmPC. 2016. 
43. 
Eisai. Full prescription information for Halaven®. 2017. 
44. 
Polyphor. Investigator's Brochure: Balixafortide. 2019;Version 11.0. 
45. 
Kaufman PA, Pernas Simon S, Martin M, et al. Balixafortide (a CXCR4 antagonist) + 
eribulin in HER2-negative metastatic breast cancer (MBC): survival outcomes of the 
phase I trial. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2019;37(Suppl 2606). 
46. 
Cortes Castan J, Martín M, Pernas S, et al. Balixafortide (a novel CXCR4 inhibitor) and 
eribulin in HER2-neg metastatic breast cancer (MBC) patients (pts): a Phase I trial. 
Annals of oncology : official journal of the European Society for Medical Oncology / 
ESMO. 2018;29(Suppl 8):viii90-viii121.10.1093/annonc/mdy272. 
47. 
Pivot X, Marme F, Koenigsberg R, Guo M, Berrak E, Wolfer A. Pooled analyses of 
erubilin in metastatic breast cancer patients with at least one prior chemotherapy. 
Annals of Oncology. 2016;27:1525-31. 
48. 
Cortes J, Vahdat L, Blum JL, Twelves C, Campone M, Roche H, et al. Phase II study 
of the halichondrin B anolog eribulin mesylate in patients with locally advanced or 
metastatic breast cancer previously treated with an anthracycline, a taxane and 
capecitabine. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2010;28(25):3922-8. 
49. 
Vahdat LT, Pruitt B, Fabian CJ, et al. Phase II study of eribulin mesylate, a halichondrin 
B anolog, in patients with metastatic breast cancer previously treated with an 
anthracycline and a taxane   Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2009;27(18):2954-61. 
50. 
Devriese LA, Witteveen PO, Wanders J, et al. Pharmacokinetics of eribulin mesylate 
in patients with solid tumours receiving repeated oral rifampicin. British journal of 
clinical pharmacology. 2012;75(2):507-15. 
51. 
Polyphor (data on file). Report no: RPT04501: Bioanalytical sample analysis report in 
support of the study entitled, “A phase I dose escalation study of POL6326 with eribulin 
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in patients with relapsed, triple negative and hormone refractory ER positive metastatic 
breast cancer. 2018. 
52. 
Sampson HA. Second Symposium on the Definition and Management of Anaphylaxis: 
Summary Report—Second National Institute of Allergy and Infectious Disease/Food 
Allergy and Anaphylaxis Network Symposium. Annals of Emergency Medicine. 
2006;47(4):373-80. 
53. 
FDA 2009. Guidance for industry. Drug-induced livery injury: premarketing clinical 
evaluation.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor
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54. 
Smith TJ, et al. Recommendations for the use of WBC growth factors: American 
Society of Clinical Oncology Clinical Practice Guideline Update Journal of Clinical 
Oncology. 2015;33(28):3199-214. 
55. 
Eisenhauer EA, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European J Cancer. 2009;45:228-74. 
56. 
Seymour L, et al. iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncology. 2017;18(3):e143-e52. 
57. 
Taplitz RA. Outpatient management of fever and neutropenia in adults treated for 
malignancy: American Society of Clinical Oncology and Infectious Diseases Society of 
America clinical practice guideline update    Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology. 2018;36(14):1443-53. 
58. 
Schiffer CA. Platelet transfusion for patients with cancer: American Society of Clinical 
Oncology clinical practice guideline update Journal of Clinical Oncology. 
2018;36(3):283-99. 
59. 
Ellis S, Carroll KJ, Pemberton K. Analysis of Duration of Response in Oncology Trials 
Contemporary Clinical Trials. 2008;29:456-65. 
60. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-55. 
 
 
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20. 
APPENDICES 
Appendix 1 Prohibited Medications 
CredibleMeds® has reviewed available evidence for the drugs on the following list and categorized 
them as drugs of Known Risk (KR) of torsades de pointes (TdP). The full description of these categories 
can be found on the CredibleMeds.org website. For a complete and most up-to-date drug list, please 
check the website at: https://www.crediblemeds.org/healthcare-providers/drug-list 
Generic Name 
Brand Name 
Aclarubicin (KR) 
Aclacin and others 
Amiodarone (KR) 
Cordarone® and others 
Anagrelide (KR) 
Agrylin® and others 
Arsenic trioxide (KR) 
Trisenox® 
Astemizole (KR) 
Hismanal® 
Azithromycin (KR) 
Zithromax® and others 
Bepridil (KR) 
Vascor® 
Chloroquine (KR) 
Aralen® 
Chlorpromazine (KR) 
Thorazine® and others 
Cilostazol (KR) 
Pletal® 
Ciprofloxacin (KR) 
Cipro® and others 
Cisapride (KR) 
Propulsid® 
Citalopram (KR) 
Celexa® and others 
Clarithromycin (KR) 
Biaxin® and others 
Cocaine (KR) 
Cocaine 
Disopyramide (KR) 
Norpace® 
Dofetilide (KR) 
Tikosyn® 
Domperidone (KR) 
Motilium® and others 
Donepezil (KR) 
Aricept® 
Dronedarone (KR) 
Multaq® 
Droperidol (KR) 
Inapsine® and others 
Erythromycin (KR) 
E.E.S.® and others 
Escitalopram (KR) 
Cipralex® and others 
Flecainide (KR) 
Tambocor® and others 
Fluconazole (KR) 
Diflucan® and others 
Gatifloxacin (KR) 
Tequin® 
Grepafloxacin (KR) 
Raxar® 
Halofantrine (KR) 
Halfan® 
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Generic Name 
Brand Name 
Haloperidol (KR) 
Haldol® [US & UK] and others 
Hydroxyquinidine, dihydroxyquinidine (KR) 
Serecor® 
Ibogaine (KR) 
None 
Ibutilide (KR) 
Corvert® 
Levofloxacin (KR) 
Levaquin® and others 
Levomepromazine 
(methotrimeprazine) 
(KR) 
Nosinan® and others 
Levomethadyl acetate (KR) 
Orlaam® 
Levosulpiride (KR) 
Lesuride® and others 
Mesoridazine (KR) 
Serentil® 
Methadone (KR) 
Dolophine® and others 
Moxifloxacin (KR) 
Avelox® and others 
Ondansetron (KR) 
Zofran® and others 
Oxaliplatin (KR) 
Eloxatin® 
Papaverine HCl (Intracoronary) (KR) 
none 
Pentamidine (KR) 
Pentam® 
Pimozide (KR) 
Orap® 
Probucol (KR) 
Lorelco® 
Procainamide (KR) 
Pronestyl® and others 
Propofol (KR) 
Diprivan® and others 
Quinidine (KR) 
Quinaglute® and others 
Roxithromycin (KR) 
Rulide® and others 
Sevoflurane (KR) 
Ultane® and others 
Sotalol (KR) 
Betapace® and others 
Sparfloxacin (KR) 
Zagam® 
Sulpiride (KR) 
Dogmatil® and others 
Sultopride (KR) 
Barnetil® and others 
Terfenadine (KR) 
Seldane® 
Terlipressin (KR) 
Teripress® and others 
Terodiline (KR) 
Micturin® and others 
Thioridazine (KR) 
Mellaril® and others 
Vandetanib (KR) 
Caprelsa® 
KR: known risk of torsades de pointes; UK: United Kingdom; US: United States 
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Appendix 2 ECOG Performance Status  
These scales and criteria are used by doctors and researchers to assess how a patient's 
disease is progressing, assess how the disease affects the daily living abilities of the patient, 
and determine appropriate treatment and prognosis. They are included here for health care 
professionals to access. 
ECOG Performance Status* 
Grade 
ECOG 
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 selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
Source: (60) 
 
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Appendix 3 Summary of RECIST v1.1 Guidelines 
This summary is based on the RECIST v1.1 guidelines which should be consulted for further 
details (55). 
Measurability of Tumors at Baseline 
All measurements should be recorded in metric notation using calipers if clinically assessed. 
Measurable Tumor Lesions 
Tumor lesions must be measured accurately in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:  
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 
10 mm caliper measurement by clinical examination (lesions which cannot be 
measured accurately with calipers should be recorded as non-measurable). 
• 
20 mm by chest X-ray. 
Measurable Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be P15 mm in 
the short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and during follow-up, only the short axis will be measured and 
followed. 
Non-measurable Tumor Lesions or Lymph Nodes 
These are all other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with P10 to <15 mm short axis), as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
Baseline Documentation of 'Target' and 'Non-target' Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions in total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions, and will be recorded and measured at baseline. This 
means that in patients who have only 1 or 2 organ sites involved, a maximum of 2 and 4 
lesions will be recorded respectively. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, and should be those that lend themselves to 
reproducible repeated measurements. In cases where the largest lesion does not lend itself 
to reproducible measurement, the next largest lesion that can be measured reproducibly 
should be selected.   
 
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Lymph Nodes 
Pathological lymph nodes which are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of P15 mm by CT scan. Only the short axis of 
these nodes will contribute to the baseline sum. The short axis of the node is the diameter 
normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT scan 
this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or 
coronal). The smaller of these measures is the short axis. For example, an abdominal node 
which is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis P10 mm but <15 mm) should 
be considered non-target lesions. Nodes that have a short axis <10 mm are considered non-
pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to 
be included in the sum, then as noted above, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response Criteria 
Assessment of Target Lesions  
The RECIST v1.1 definitions of the criteria used to determine tumor response for target lesions 
are provided in Table 5, Section 8.2.2. 
(i) Lymph nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of <10 mm. CRFs or other data collection methods may therefore be designed to have 
target nodal lesions recorded in a separate section where, in order to qualify for CR, each 
node must achieve a short axis <10 mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
(ii) Target lesions that become ‘too small to measure’: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan 
that the radiologist may not feel comfortable assigning an exact measure and may report them 
as being ‘too small to measure’. When this occurs, it is important that a value is recorded on 
the CRF. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly 
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seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable size when 
normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a 
lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived 
from the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). 
The measurement of these lesions is potentially non-reproducible, therefore, providing this 
default value will prevent false responses or progressions based upon measurement error. To 
reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm. 
(iii) Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion. If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Assessment of Non-target Lesions  
The RECIST v1.1 definitions of the criteria used to determine tumor response for non-target 
lesions are provided in Table 6, Section 8.2.2. 
While some non-target lesions may be measurable, they need not be measured and instead 
should be assessed qualitatively only at the time points specified in the protocol. 
Assessing progression of non-target disease is described below: 
(i) When the patient also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in the presence of SD or PR in target disease, 
the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. The designation of overall progression solely on 
the basis of change in non-target disease in the face of SD or PR of target disease will, 
therefore, be extremely rare. 
(ii) When the patient has only non-measurable disease: This circumstance arises in some 
Phase 3 trials when it is not a criterion of study entry to have measurable disease. The same 
general concepts apply here as noted above, however, in this instance there is no measurable 
disease assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified (by definition: if 
all lesions are truly non-measurable) a useful test that can be applied when assessing patients 
for unequivocal progression is to consider if the increase in overall disease burden based on 
the change in non-measurable disease is comparable in magnitude to the increase that would 
be required to declare PD for measurable disease: i.e. an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase 
diameter in a measurable lesion). Examples include an increase in a pleural effusion from 
‘trace’ to ‘large’, an increase in lymphangitic disease from localized to widespread. If 
‘unequivocal progression’ is seen, the patient should be considered to have had overall PD at 
that point. While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so, therefore, the increase 
must be substantial. 
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(iii) New Lesions: The appearance of new malignant lesions denotes disease progression; 
therefore, some comments on detection of new lesions are important. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal: i.e. not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the patient’s baseline lesions show PR or CR. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which 
it is not. 
A lesion identified in an anatomical location that was not scanned at baseline is considered a 
new lesion and will indicate disease progression. An example of this is the patient who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals 
metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial 
scan. 
While 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) response 
assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-
PET scanning to complement CT scanning in assessment of progression (particularly possible 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according to 
the following algorithm: 
o Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
o No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD. 
l A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the 
surrounding tissue on the attenuation corrected image. 
 
Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. The patient’s 
best overall response assignment will depend on the findings of both target and non-target 
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disease and will also take into consideration the appearance of new lesions. Furthermore, it 
will require confirmation as outlined in Section 8.2.2.  
Timepoint Response  
Table 7 (Section 8.2.2) provides a summary of the overall response calculation that is to be 
used at each response assessment timepoint specified in the Study Schedule for patients who 
have measurable disease at baseline. When patients have non-measurable (i.e. non-target) 
disease only, Table 8 (Section 8.2.2) is to be used. 
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable (NE) at that timepoint. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that timepoint, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned timepoint response. This would be most likely to happen in the case of 
PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will 
have achieved PD status, regardless of the contribution of the missing lesion. 
Best Overall Response where Confirmation of CR or PR Required 
The best overall response is determined once all the data for the patient is known. 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent timepoint as specified in the protocol (i.e. at least 4 weeks later). In this 
circumstance, the best overall response can be interpreted as shown in Table 17. 
 
Table 17 
Best overall response when confirmation of CR and PR required 
Overall Response at first 
timepoint 
Overall Response at 
subsequent timepoint 
(i.e. at least 4 weeks 
after first timepoint) 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR 
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Overall Response at first 
timepoint 
Overall Response at 
subsequent timepoint 
(i.e. at least 4 weeks 
after first timepoint) 
Best Overall Response 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
CR: complete response; PD: progressive disease; NE: not evaluable; PR: partial response; SD: stable disease 
Source: (55) 
a: If a CR is truly met at first timepoint, then any disease seen at a subsequent timepoint, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes `CR' may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first timepoint. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.    
 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on an increase in size of the nodes. This means that patients 
with CR may not have a total sum of ‘zero’ on the eCRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Table 7, Table 8 and Table 17. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. 
Both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
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assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
 
 
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Appendix 4 Summary of iRECIST Guidelines 
This summary is based on the iRECIST guidelines (56). 
iRECIST is based on RECIST v1.1. Responses assigned using iRECIST have a prefix of “i” 
(i.e. immune)—e.g. “immune” complete response (iCR) or partial response (iPR), and 
unconfirmed progressive disease (iUPD) or confirmed progressive disease (iCPD) to 
differentiate them from responses assigned using RECIST 1.1. Similar nomenclature is used 
for stable disease (iSD). New lesions are assessed and subcategorized into those that qualify 
as target lesions (new lesion, target) or non-target lesions (new lesion, non-target). 
The continued use of RECIST v1.1 is recommended to define whether tumor lesions (including 
lymph nodes) are measurable or non-measurable, as well as for the management of bone 
lesions, cystic lesions, and lesions with previous local treatment. The principles for 
establishing objective tumor response are similar to RECIST v1.1, but the main change for 
iRECIST is the action to be taken if RECIST v1.1 progression is followed at the next 
assessment by tumor shrinkage.  
iRECIST defines iUPD in a similar way to RECIST v1.1 guidance, however, iUPD requires 
confirmation, by observing either a further increase in size (or in the number of new lesions) 
in the lesion category in which progression was first identified (i.e. target or non-target 
disease), or progression (defined by RECIST v1.1) in lesion categories that had not previously 
met RECIST v1.1 progression criteria. However, if progression is not confirmed, but instead 
tumor shrinkage occurs (compared with baseline), which meets the criteria for iCR, iPR, or 
iSD, then the bar is reset so that iUPD needs to occur again (compared with nadir values) and 
then be confirmed (by further growth) at the next assessment for iCPD to be assigned. If no 
change in tumor size or extent occurs from iUPD, then the timepoint response would again be 
iUPD. This approach allows atypical responses, such as delayed responses that occur after 
pseudoprogression, to be identified.    
Assessment of Target, Non-target, and New Lesions 
Most RECIST v1.1 recommendations are unchanged for timepoint response, including the 
management of lymph nodes, lesions that become too small to measure, lesions that split or 
coalesce, and the definition of CR, PR, SD, and PD. Each timepoint response is based on the 
assessment of target lesions, non-target lesions, and new lesions. 
For target lesions, iCR, iPR, and iSD can all be assigned after iUPD has been documented, 
as long as iCPD was not confirmed. iUPD is defined by RECIST v1.1 criteria for PD; iUPD can 
be assigned multiple times as long as iCPD is not confirmed at the next assessment. 
Progression is confirmed in the target lesion category if the next imaging assessment after 
iUPD (at least 6 weeks later in this study) confirms a further increase in sum of measures of 
target disease from iUPD, with an increase of at least 5 mm. However, the criteria for iCPD 
(after iUPD) are not considered to have been met if CR, PR, or SD criteria (compared with 
baseline and as defined by RECIST v1.1) are met at the next assessment after iUPD. The 
status is reset (unlike RECIST v1.1, in which any progression precludes later CR, PR, or SD). 
iCR, iPR, or iSD should then be assigned; and if no change is detected, then the timepoint 
response is iUPD. 
The assessment of non-target lesions at each timepoint follows similar principles. iUPD (but 
not iCPD) can be documented before iCR or when the criteria for neither CR nor PD have 
been met (referred to as non-iCPD/non-iUPD) and can be assigned several times, as long as 
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iCPD was not confirmed. iUPD is defined by RECIST v1.1 criteria; however, iUPD can be 
assigned multiple times as long as iCPD is not confirmed at the next assessment. 
PD in the non-target lesion category is confirmed if subsequent imaging, done at least 6 weeks 
after iUPD in this study, shows a further increase from iUPD. The criteria for iCPD are not 
judged to have been met if RECIST v1.1 criteria for CR or non-iCR/non- iUPD are met after a 
previous iUPD. The status is reset (unlike RECIST v1.1) and iCR, or non-iCR/non-iUPD is 
assigned; if no change is detected, the timepoint response is iUPD. 
RECIST v1.1 defines the appearance of new malignant lesions as denoting true disease 
progression, providing that other lesions (artefacts or benign intercurrent disease) are 
assessed appropriately and discounted if not malignant. These principles of RECIST v1.1 
remain useful and clearly identify the management of new lesions that are considered to be 
potentially artefactual: “If a new lesion is equivocal, for example because of its small size, 
continued therapy and follow-up assessment will clarify whether it represents truly new 
disease. If repeat scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan”. 
However, many aspects of new lesion assessment are unique to iRECIST. If a new lesion is 
identified (thus meeting the criteria for iUPD) and the patient is clinically stable, treatment 
should be continued. New lesions should be assessed and categorized as measurable or non- 
measurable using RECIST v1.1 principles. Five lesions (no more than 2 per organ) should be 
measured and recorded as a new lesion target, but should not be included in the sum of 
measures of the original target lesions identified at baseline. Other measurable and non-
measurable lesions are recorded as new lesion non-target. New lesions do not need to meet 
the criteria for new lesion target to result in iUPD (or iCPD); new lesion non-target can also 
drive iUPD or iCPD. iCPD is assigned to the new lesion category if the next imaging 
assessment, done at 4–8 weeks after iUPD, confirms additional new lesions or a further 
increase in new lesion size from iUPD (sum of measures increase in new lesion target ≥5 mm, 
any increase for new lesion non-target). 
Notably, if iUPD criteria were met on the basis of progression in the target or non-target 
disease, or the appearance of new lesions, then RECIST v1.1-assigned progression in 
another lesion category in the confirmatory scan also confirms iCPD. 
Continued Treatment after iUPD 
The existing literature describes pseudoprogression as an increase in the size of lesions, or 
the visualization of new lesions, followed by a response, which might be durable. 
Differentiating transient pseudoprogression from true progression can be challenging. 
Although early discontinuation of an effective drug is not desirable, continued long-term 
treatment with a non-effective drug past true progression might delay the initiation of 
potentially effective salvage therapy. 
An assignment of clinical stability requires that there is no worsening of performance status, 
that there are no clinically relevant increases in disease-related symptoms (e.g. pain or 
dyspnea) that are thought to be associated with disease progression (generally understood to 
mean a requirement for increased palliative intervention), and that there is no requirement for 
intensive management of disease-related symptoms (including increased analgesia, 
radiotherapy, or other palliative care). 
The imaging findings and the recommendation to continue with treatment despite iUPD should 
be discussed with the patient before a decision is made about whether to continue therapy. 
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Patients who have iUPD and are not clinically stable should be designated as not clinically 
stable in the eCRF. This designation will allow the best overall response to be calculated and 
the date of iUPD to be used in estimates of PFS. 
If the confirmatory scan confirms iCPD, but the Investigator or patient believes that continued 
treatment is appropriate, imaging should continue, and data should be collected to allow 
further elucidation of tumor growth dynamics with immune modulators. For the same reason, 
and if feasible, even patients who discontinue therapy for iCPD are recommended to continue 
to have disease assessments until they start other systemic or local therapies. 
Timepoint and Best Overall Response 
Although the principles of assigning the timepoint response and best overall response closely 
follow RECIST v1.1, and reflect assessment of target and non-target lesions as well as the 
presence of new lesions, the possibility of pseudoprogression adds complexity. The timepoint 
response is calculated using the response assigned for each category of lesion (as for RECIST 
v1.1), but takes into account the last timepoint response (Table 18). 
Table 18 
Key Principles to Consider 
Have criteria for 
iUPD been met? 
Principles to consider 
No 
Follow RECIST V1.1 guidance 
Yes 
Next timepoint response could be:   
• 
iUPD (no change noted in any category of lesion) 
• 
iSD, iPR, or iCR, Here, iUPD (followed by iCPD) should occur again 
• 
iCPD (if the category in which iUPD was met at the last timepoint response 
shows a further increase in tumor burden as evidenced [as applicable] by a 
≥5 mm increase in sum of measures of target or new target lesions, further 
increase in non-target or new non-target lesions, or an increase in the 
number of new lesions 
iCPD: immune confirmed progression; iCR: immune complete response; iPR: immune partial response; iSD: 
immune stable disease; iUPD: immune unconfirmed progression; RECIST: Response Evaluation Criteria In Solid 
Tumors. 
The algorithm for patients with no previous iUPD is identical to RECIST v1.1.  
For patients with iUPD at the last timepoint response, the next timepoint response is 
dependent on the status of all lesions (including target, non-target, new lesion target, and new 
lesion non-target), on whether any increase in size has occurred (either a further increase in 
size or a sufficient increase to assign a new iUPD if the criteria were not previously met), or 
the appearance of additional new lesions. 
For iRECIST, the immune best overall response (iBOR) is the best timepoint response 
recorded from the start of the study treatment until the end of treatment, taking into account 
any requirement for confirmation. iUPD will not override a subsequent best overall response 
of iSD, iPR, or iCR (Table 19), this means that iPR or iSD can be assigned (timepoint response 
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or iBOR) even if new lesions have not regressed, or if unequivocal progression (non-target 
lesions) remains unchanged, providing that the criteria for iCPD are not met. 
Table 19 
Assignment of Timepoint Response Using iRECIST 
 
 
                  Timepoint Response 
 
No 
previous 
iUPD in any 
category 
Previous iUPD in any category* 
Target lesions: iCR 
Non-target lesions: iCR 
New lesions: no 
iCR 
iCR 
Target lesions: iCR 
Non-target lesions:               non-
iCR/non-iUPD 
New lesions: no 
iPR 
iPR 
Target lesions: iPR 
Non-target lesions:              non-
iCR/non-iUPD 
New lesions: no 
iPR 
iPR 
Target lesions: iSD 
Non-target lesions:              non-
iCR/non-iUPD 
New lesions: no 
iSD 
iSD 
Target lesions: iUPD with no 
change, or with a decrease from 
last timepoint 
Non-target lesions: iUPD with no 
change, or decrease from last 
timepoint 
New lesions: yes 
Not applicable 
New lesions confirm iCPD if new lesions were previously 
identified and they have increased in size (≥5 mm in sum of 
measures for new lesion target or any increase for new lesion 
non-target) or number; if no change is seen in new lesions 
(size or number) from last timepoint, assignment remains 
iUPD 
Target lesions: iSD, iPR, iCR 
Non-target lesions: iUPD 
New lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis of a 
further increase in the size of non-target disease (does not 
need to meet RECIST v1.1 criteria for unequivocal 
progression) 
Target lesions: iUPD 
IUPD 
Remains iUPD unless iCPD is confirmed on the basis of a 
further increase in sum of measures ≥5 mm; otherwise, 
assignment remains iUPD 
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                  Timepoint Response 
 
No 
previous 
iUPD in any 
category 
Previous iUPD in any category* 
Non-target lesions:               non-
iCR/non-iUPD, or iCR 
New lesions: no 
Target lesions: iUPD 
Non-target lesions: iUPD 
New lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed based on a further 
increase in previously identified target lesion iUPD in sum of 
measures ≥5 mm or non-target lesion iUPD (previous 
assessment need not have shown unequivocal progression) 
Target lesions: iUPD 
Non-target lesions: iUPD 
New lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis of a further 
increase in previously identified target lesion iUPD sum of 
measures ≥5 mm, previously identified non-target lesion iUPD 
(does not need to be unequivocal), or an increase in the size or 
number of new lesions previously identified 
Target 
lesions: 
non-iUPD 
or 
progression 
Non-target lesions: non-iUPD or 
progression 
New lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis of an 
increase in the size or number of new lesions previously 
identified 
iCPD: immune confirmed progression; iCR: immune complete response; iPR: immune partial response; iSD: immune stable 
disease; iUPD: immune unconfirmed progression; non-iCR/non-iUPD: criteria for neither immune CR nor PD have been met; 
RECIST: Response Evaluation Criteria In Solid Tumors. 
Target lesions, non-target lesions, and new lesions defined according to RECIST v1.1 principles; if no pseudoprogression occurs, 
RECIST v1.1 and iRECIST categories for complete response, partial response, and stable disease would be the same.  
*Previously identified in assessment immediately before this timepoint.  
“i” indicates immune responses assigned using iRECIST. 
 
The duration of iCR and iPR is calculated from the timepoint when the criteria for iCR or iPR 
are first met, whereas the duration of iSD is calculated from baseline. 
Assessments that are not done or are NE should be disregarded. For example, an iUPD 
followed by an assessment that was not done or NE, and then another unconfirmed 
progressive disease, would be indicative of iCPD.  
Progression Free Survival 
The event date to be used for calculation of iPFS should be the first date at which progression 
criteria are met (i.e. the date of iUPD) provided that iCPD is confirmed at the next assessment. 
If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, that iUPD date should 
not be used as the progression event date. 
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If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, then the iUPD 
date should still be used in the following scenarios: if the patient stops protocol treatment 
because they were not judged to be clinically stable, or no further response assessments are 
done (because of patient refusal, protocol non-compliance, or patient death); the next 
timepoint responses are all iUPD, and iCPD never occurs; or the patient dies from their cancer. 
The eCRF collects the reason why confirmatory response assessment was not done at any 
timepoint, such as not clinically stable, center error, patient refusal, or patient death.
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Appendix 5 Scales and Assessments 
Body surface area will be calculated according to the following formula: 
Body surface area {m2} = ([Height {cm} x Weight {kg}]/3600)1⁄2 
 
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Appendix 6 Prescribing Information and Labels for Eribulin 
See separate attachments 
  
 
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Appendix 7 ASCO Guidance on the Use of CSFs 
See separate attachment and also reference (54). 
 
 
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Appendix 8 ASCO Guidance on Outpatient Management of Fever and 
Neutropenia in Patients Treated for Malignancy 
See separate attachments and reference (57). 
 
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Appendix 9 ASCO Guidance on Platelet Transfusions for Patients with Cancer 
See separate attachments and reference (58). 
 
 
 
 
 
 
 
 
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Appendix 10 Any Additional Study Information that the Patient will Receive 
See separate attachments 
 
 
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Appendix 11 Quality of Life Patient Questionnaires 
See separate attachments 
 
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Polyphor Ltd 
POL6326-009 
An International, Phase 3, Multicenter, Randomized, Open-Label Trial 
Comparing Balixafortide in combination with Eribulin versus Eribulin alone 
in Patients with HER2 negative Locally Recurrent or Metastatic Breast 
Cancer 
 
14MAY2021 
 
Statistical Execution Plan 
 
Version 1.0 
Prepared by: 
PPD 
Granta Park, Great Abington 
Cambridge, CB21 6GQ 
UK 
62


  
PPD Biostatistics and Programming 
Statistical Analysis Plan (SAP) Client Approval Form 
 
PPD CONFIDENTIAL AND PROPRIETARY 
SOP-BST-05ar06  
Effective Date:   19 September 2019 
Page 1 of 1 
Client: 
Polyphor Ltd 
Protocol Number: 
POL6326-009 
 
Document Description: 
Final Statistical Execution Plan (FDA) 
SAP Title: 
An International, Phase 3, Multicenter, Randomized, 
Open-Label Trial Comparing Balixafortide in combination 
with Eribulin versus Eribulin alone in Patients with HER2 
negative Locally Recurrent or Metastatic Breast Cancer 
SAP Version Number: 
1.0 
Effective Date: 
14 May 2021 
 
Author(s): 
For PPD: Gabriele Lapini, Biostatistician II 
 
Approved by: 
 
 
 
Stéphane Lavigne, Principal Biostatistician 
Biostatistics, PPD 
 
Date (DD-MMM-YYYY) 
 
 
 
Kevin J Carroll, Statistician 
KJC Statistics Ltd 
 
Date (DD-MMM-YYYY) 
 
 
 
Frank Weber, CMO 
Polyphor Ltd. 
 
Date (DD-MMM-YYYY) 
 
 
20 May 2021
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
1. 
INTRODUCTION ............................................................................................................ 7 
2. 
OBJECTIVES ................................................................................................................... 7 
2.1. PRIMARY OBJECTIVE ..................................................................................................................................... 7 
2.2. SECONDARY OBJECTIVES ............................................................................................................................. 7 
2.3. EXPLORATORY OBJECTIVES ........................................................................................................................ 7 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 8 
3.1. OVERALL STUDY DESIGN AND PLAN ....................................................................................................... 8 
3.2. STUDY ENDPOINTS ....................................................................................................................................... 10 
3.2.1. 
Co-Primary Efficacy Endpoint .................................................................................. 10 
3.2.2. 
Key Secondary Efficacy Endpoint ............................................................................. 10 
3.2.3. 
Other Secondary Efficacy Endpoints ........................................................................ 10 
3.2.4. 
Secondary Safety Endpoints ...................................................................................... 10 
3.2.5. 
Exploratory Efficacy Endpoints ................................................................................ 11 
3.3. TREATMENTS ................................................................................................................................................. 11 
3.3.1. 
Balixafortide + eribulin ............................................................................................ 11 
3.3.2. 
Eribulin monotherapy ............................................................................................... 11 
3.4. DOSE ADJUSTMENT/MODIFICATIONS .................................................................................................... 12 
3.4.1. 
Dose Modification Balixafortide ............................................................................... 12 
3.4.2. 
Dose Modification Eribulin ...................................................................................... 12 
3.4.3. 
Dosing Delays or Interruptions ................................................................................ 12 
4. 
GENERAL STATISTICAL CONSIDERATIONS ...................................................... 13 
4.1. SAMPLE SIZE .................................................................................................................................................. 14 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ....................................................................... 14 
4.3. ANALYSIS SET ............................................................................................................................................... 15 
4.3.1. 
Enrolled Set ............................................................................................................... 15 
4.3.2. 
Intent-to-Treat Set ..................................................................................................... 15 
4.3.3. 
Intent-to-Treat Set (3rd Line+) .................................................................................. 15 
4.3.4. 
Intent-to-Treat Set (3rd Line+ Confirmed) ................................................................ 16 
4.3.5. 
Per-Protocol Set (3rd Line+ Confirmed) ................................................................... 16 
4.3.6. 
Response Evaluable Set (3rd Line+) .......................................................................... 16 
4.3.7. 
Response Evaluable Set (3rd Line+ Confirmed) ........................................................ 16 
4.3.8. 
Patient Reported Outcome Set (3rd Line+) ............................................................... 16 
4.3.9. 
Safety Set ................................................................................................................... 17 
4.3.10. 
Safety Set (3rd Line+) ............................................................................................. 17 
4.4. HANDLING OF MISSING OR PARTIAL DATE DATA ............................................................................ 17 
4.5. MAPPING OF UNSCHEDULED VISITS ....................................................................................................... 19 
4.6. COVID-19 IMPACT ..................................................................................................................................... 19 
5. 
PATIENT DISPOSITION .............................................................................................. 20 
5.1. DISPOSITION ................................................................................................................................................... 20 
5.2. PROTOCOL DEVIATIONS ............................................................................................................................. 20 
5.3. MISSED VISITS DUE TO COVID-19 ................................................................................... 20 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 20 
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6.1. MEDICAL HISTORY ...................................................................................................................................... 21 
6.1.1. 
General Medical History .......................................................................................... 21 
6.1.2. 
Breast Cancer History .............................................................................................. 21 
6.1.3. 
Prior Anti-Cancer Therapy ....................................................................................... 21 
6.1.4. 
Previous Radiotherapy and Surgical History ........................................................... 22 
6.2. INCLUSION AND EXCLUSION CRITERIA ................................................................................................. 22 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 22 
7.1. PRIOR AND CONCOMITANT MEDICATIONS .......................................................................................... 22 
7.2. POST ANTI-CANCER THERAPY ................................................................................................................ 23 
7.3. STUDY TREATMENTS .................................................................................................................................. 23 
7.3.1. 
Extent of Exposure .................................................................................................... 23 
7.3.2. 
Treatment Compliance and Modifications ................................................................ 23 
8. 
EFFICACY ANALYSIS. ................................................................................................ 24 
8.1. CO-PRIMARY EFFICACY ENDPOINT ....................................................................................................... 24 
8.1.1. 
Progression-Free Survival ........................................................................................ 24 
8.1.2. 
Objective Response Rate ........................................................................................... 25 
8.1.3. 
Primary Analysis ....................................................................................................... 26 
8.1.3.1. 
Sensitivity Analysis for PFS ................................................................................... 27 
8.2. KEY SECONDARY EFFICACY ENDPOINT ANALYSIS .......................................................................... 27 
8.3. TIMING OF ANALYSES OF PRIMARY AND KEY SECONDARY EFFICACY ENDPOINTS AND 
TYPE I ERROR CONTROL ......................................................................................................................................... 28 
8.4. OTHER SECONDARY ENDPOINTS ............................................................................................................ 28 
8.4.1. PFS Assessed by Local Investigator's Review..................................................................28 
8.4.2. ORR Assessed by Local Investigator's Review….............................................................29 
8.4.3. 
Clinical Benefit Rate ................................................................................................. 29 
8.4.4. 
Disease Control Rate ................................................................................................ 29 
8.4.5. 
Time to Response ...................................................................................................... 29 
8.4.6. 
Duration of Response ................................................................................................ 30 
8.5. EXPLORATORY EFFICACY ENDPOINTS .................................................................................................. 30 
8.5.1. 
EORTC-QLQ-C30 QoL ............................................................................................ 32 
8.5.2. 
EQ-5D ....................................................................................................................... 33 
8.5.3. 
FACT-B ..................................................................................................................... 34 
8.5.4. 
Relationship between biomarkers and clinical outcomes ......................................... 35 
8.5.5. 
Response in patient who continue study treatment despite progression ................... 35 
8.5.6. 
Baseline Tumor Samples ........................................................................................... 35 
9. 
SAFETY ANALYSIS ..................................................................................................... 35 
9.1. ADVERSE EVENTS ........................................................................................................................................ 35 
9.1.1. 
Incidence of Adverse Events ..................................................................................... 36 
9.1.2. 
Severity of Adverse Event .......................................................................................... 37 
9.1.3. 
Serious Adverse Events ............................................................................................. 37 
9.1.4. 
Relationship of Adverse Events to Study Treatment ................................................. 37 
9.1.5. 
Adverse Events Leading to Study Treatment Discontinuation .................................. 37 
9.1.6. 
Deaths ....................................................................................................................... 37 
9.1.7. 
Subgroup Evaluation of Adverse Events ................................................................... 38 
9.1.8. 
Adverse Events of Special and Adverse Events of Particular Interest ...................... 38 
9.2. CLINICAL LABORATORY EVALUATIONS .............................................................................................. 39 
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9.2.1. 
Hematology ............................................................................................................... 39 
9.2.2. 
Biochemistry ............................................................................................................. 39 
9.2.3. 
Urinalysis .................................................................................................................. 40 
9.3. VITAL SIGN MEASUREMENTS .................................................................................................................. 40 
9.4. PHYSICAL EXAMINATION .......................................................................................................................... 40 
9.5. ELECTROCARDIOGRAM .............................................................................................................................. 40 
9.6. OTHER SAFETY DATA ................................................................................................................................. 42 
9.6.1. 
Medication Errors ..................................................................................................... 42 
9.6.2. 
ECOG Performance Score ........................................................................................ 42 
9.6.3. 
Exposure during pregnancy ...................................................................................... 42 
10. 
PHARMACOKINETICS ............................................................................................... 42 
11. 
INTERIM ANALYSIS ................................................................................................... 42 
12. 
CHANGES IN THE PLANNED ANALYSIS............................................................... 42 
13. 
REFERENCES ................................................................................................................ 43 
14. 
APPENDICES ................................................................................................................. 45 
14.1. 
GENERAL SCHEDULE OF ASSESSMENTS ........................................................................................... 45 
14.1.1. 
Schedule of Assessments for Balixafortide + Eribulin Treatment Arm ................. 45 
14.1.2. 
Schedule of Assessments for Eribulin Monotherapy Treatment Arm .................... 51 
14.2. 
TYPE I ERROR CONTROL FOR PRIMARY AND KEY SECONDARY EFFICACY ANALYSES .... 55 
14.3. 
SCORING FOR QLQ-C30 VERSION 3.0 ........................................................................... 56 
14.4. 
SUBSCALE SCORING FOR THE FACT-B ......................................................................... 57 
14.5. 
ALGORITHM FOR THE BEST RESPONSE DETERMINATION ACCORDING TO RECIST V1.1 
GUIDELINES, AS ASSESSED BY THE LOCAL INVESTIGATOR'S REVIEW ....................................................... 58 
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List of Abbreviations 
AE 
Adverse Event 
AEPI 
Adverse Event of Particular Interest 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
analysis of covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CBR 
CI 
Clinical Benefit Rate 
Confidence interval 
CISH 
Chromogenic In Situ Hybridization 
CR 
Complete Response 
CSP 
Colony Stimulating Factor 
CT 
CXCR4 
DCR 
Computed Tomography 
C-X-C Chemokine Receptor Type 4 
Disease Control Rate 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
FACT-B 
Functional Assessment of Cancer Therapy - Breast 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in Situ Hybridization 
GCP 
Good Clinical Practice 
HEENT 
HER2 
head, ears, eyes, nose, throat 
Human Epidermal Growth Factor Receptor 2 
HR 
Hormone Receptor 
HRQoL 
Health-Related Quality of Life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IRC 
Independent Review Committee 
IRT 
Interactive Response Technology 
iRECIST 
Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer 
immunotherapy trials 
ITT 
Intent-To-Treat 
IV 
Intravenous 
KM 
Kaplan-Meier 
MBC 
Metastatic Breast Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
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MRI 
Magnetic Resonance Imaging 
NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events 
NE 
Not Evaluable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PE 
Physical Exam 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PR 
Partial Response 
PRO 
Patient Reported Outcome 
PT 
preferred term 
QoL 
Quality of Life 
RE 
Response Evaluable 
RECIST 
REML 
Response Evaluation Criteria in Solid Tumors 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to Maximum Concentration 
TNBC 
Triple-Negative Breast Cancer 
ULN 
Upper Limit of Normal 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
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1. Introduction 
This document describes the planned statistical analyses of the data captured in Polyphor Ltd. 
protocol POL6326-
-Label Trial 
Comparing Balixafortide in combination with Eribulin versus Eribulin alone in Patients with 
ocol Version 3.0, 15 
July 2019. This Phase III trial is conducted in accordance with the protocol, Good Clinical Practice 
(GCP) and all applicable regulatory requirements. 
The data from protocol POL6326-009 will serve a dual purpose: (i) to provide efficacy and 
safety data in the 3rd line+ patient population of patients with locally recurrent or metastatic breast 
cancer primarily for regulatory submissions in the US and jurisdictions in which the 3rd line+ 
eribulin label applies and (ii) to provide efficacy and safety data in the overall population of 
patients who receive study treatment in the 2nd line+ patient population , for regulatory 
submissions in the EU and jurisdictions in which the 2nd line+ eribulin label applies. 
This execution plan describes the analyses and data summaries in relation with the 3rd line+ 
population. 
 
2. Objectives 
 
2.1. Primary Objective 
The primary objective of the trial in the 3rd line+ population of patients with locally recurrent or 
Metastatic Breast Cancer (MBC) is to evaluate the efficacy of balixafortide + eribulin versus 
eribulin monotherapy on the co-primary endpoints of objective response rate (ORR) and 
progression free survival (PFS). 
 
2.2. Secondary Objectives 
In the 3rd line+ population of patients, secondary objectives are: 
 
To compare the overall survival (OS) between patients in the balixafortide + eribulin 
treatment arm versus eribulin monotherapy treatment arm. 
To compare measures of tumor response between patients in the balixafortide + eribulin 
treatment arm versus eribulin monotherapy treatment arm. 
To evaluate the safety and tolerability of balixafortide + eribulin versus eribulin 
monotherapy. 
 
2.3. Exploratory Objectives 
In the 3rd line+ population of patients, exploratory objectives are: 
To determine whether the response to treatment correlates with baseline estrogen receptor 
(ER), progesterone receptor (PgR) or C-X-C Chemokine Receptor Type 4 (CXCR4) 
expression level. 
To assess tumor tissue and circulating biomarkers and possible association with patient 
treatment outcome (i.e response or anti-tumor efficacy). 
To explore immune response, as assessed by Response Evaluation Criteria in Solid 
Tumours (RECIST version 1.1) in cancer immunotherapy trials (iRECIST). 
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Measurement of plasma concentration of balixafortide and potential metabolites to 
integrate in a population PK model. 
To assess the Quality of Life (QoL) as reported by patients in the balixafortide + eribulin 
treatment arm versus eribulin monotherapy treatment arm using standard QoL 
assessments. 
 
3. Investigational Plan 
 
3.1. Overall Study Design and Plan 
This is an open-label, 1:1 randomized, two-arm, multi-center, international pivotal Phase 3 trial 
designed to investigate the efficacy and safety of balixafortide in combination with eribulin 
relative to eribulin alone in patients with Human Epidermal Growth Factor Receptor 2 (HER2) 
negative, locally recurrent or metastatic BC that have previously been treated with one to four 
chemotherapeutic regimens for metastatic disease. Patients will have previously received an 
anthracycline and a taxane treatment. 
Patients will be stratified according to: 
Line of therapy (2nd line versus 3rd line or later therapy) for locally recurrent or metastatic 
BC. 
Hormone receptor (HR) status (positive versus negative) based on estrogen receptor (ER) 
or progesterone receptor (PgR) status. 
Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment received previously (received a 
CDK 4/6 inhibitor versus not received a CDK 4/6 inhibitor). 
Visceral versus non-visceral disease. Visceral metastases will include brain, pulmonary, 
pleural, hepatic and peritoneal involvement (including pleural effusions and ascites). Any 
other sites of metastases (e.g. bone, lymph nodes, and skin) will be considered to be non- 
visceral. Patients with visceral metastases, irrespective of the presence of any other 
metastatic sites (e.g. bone), will be categorized as visceral. All other patients without 
visceral metastases will be categorized as non-visceral. 
A total of 384 patients will be randomized into this trial of which 320 will be 3rd line+. As 
mentioned above, this execution plan focusses on the analysis and reporting of the 3rd line+ 
population. 
During the treatment, disease assessments will be performed every 6 weeks (±7 days) from the 
date of randomization for the first year and then every 12 weeks (±7 days) thereafter until 
Progressive Disease (PD) is documented by RECIST v1.1. 
Each assessment will be performed as scheduled according to the calendar regardless of any 
dosing delay to prevent the introduction of bias into the assessment of efficacy. Tumor 
assessments will be performed until whichever of the following occurs first: 
radiographically and/or objective (i.e., for photographed or palpable lesions) documented 
as PD per RECIST v1.1, 
discontinuation of patient from overall trial participation (e.g. death, the patient withdraws 
consent, lost to follow-up). 
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The local Investigator will assess the presence of disease following CT/MRI scan performed at 
Screening, and those performed subsequently, and record the details in the patient's source data 
and eCRF relative to the previous assessment of disease status/metastatic burden. 
A blinded Independent Review Committee (IRC) will perform a retrospective review of 
radiographic images and relevant clinical information collected on-study to assess the protocol 
defined endpoints of disease response and progression. 
Following initial documentation of an objective response, a confirmatory CT/MRI scan will be 
performed at least 4 weeks later. 
Patients discontinuing the study treatment for reasons other than death will attend an End of 
Treatment (EoT) visit as soon as possible, within 7 days after discontinuation and prior to 
initiation of any new anti-cancer therapy, regardless of the reason for discontinuation. A physical 
examination will be conducted, adverse events (AEs), Eastern Cooperative Oncology Group 
(ECOG) performance status, vital signs, clinical laboratory,12-lead Electrocardiogram (ECG), 
concomitant medications and Patient reported health outcome QoL questionnaires will be 
assessed and recorded for all patients at the EOT visit. Furthermore, tumor assessments should be 
conducted for patients who discontinued from study treatment in the absence of PD. 
A 30-day safety follow-up visit will be performed within 30 days (and no later than 37 days) from 
the last dose of study treatment. Patients discontinuing the study treatment phase for any reason, 
without PD (i.e. due to unacceptable adverse events) will enter the long-term follow-up (PD 
follow-up and survival follow-up). 
Patients who are discontinued from study treatment for any reason, in the absence of PD, will 
undergo repeat imaging and tumor response assessments every 8 weeks ±7 days (every 12 weeks 
±7 days if the patient has been on the study for >= 1 year), regardless of regimen, until PD is 
documented, or death occurs, or patient is lost to follow-up, or the patient withdraws consent 
(whichever occurs first). If a patient stops study treatment and begins another anti-cancer therapy 
before PD is documented, the new anti-cancer treatment should be recorded in the patient's source 
data and eCRF and every effort should be made to perform tumor evaluation in these patients until 
disease progression. 
All patients will be followed for OS status every 6 months until death, until the patient withdraws 
consent to follow-up for survival or until the patient is lost to follow-up (whichever occurs first). 
Patients will complete the European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) Quality of Life (QoL), Functional 
Assessment of Cancer Therapy Breast (FACT-B) and EuroQol-5D (EQ-5D) questionnaires during 
the screening period, prior to first dose, and at the start of each subsequent cycle of study treatment 
during while still in receipt of study treatment. 
An independent data safety monitoring board (DSMB) will review patient safety during the trial 
and will provide oversight of the planned, formal interim efficacy analyses. 
The enrolment period is expected to be approximately 12 months, with an expected 12 months 
further follow-up prior to the analysis of PFS and an additional 12 months follow-up thereafter to 
the final analysis of OS. The overall trial duration (from first patient randomized until the end of 
the trial) is therefore projected to be approximately 36 months. 
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3.2. Study Endpoints 
 
3.2.1. Co-Primary Efficacy Endpoint 
In the 3rd line+ population intended for regulatory submissions in the US and jurisdictions on which 
the 3rd line+ eribulin label applies, the co-primary endpoints are: 
 
ORR (confirmed CR + confirmed PR) according to RECIST v1.1 guidelines, as assessed 
by the IRC. 
PFS according to RECIST v1.1 guidelines, as assessed by the IRC. 
 
3.2.2. Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint subject to Type I error control is OS. 
 
3.2.3. Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints are considered supportive and will not be subject to overall 
Type I Error control. These endpoints are: 
PFS according to RECIST v1.1 guidelines, as assessed by the local Investigator's review. 
ORR (confirmed CR + confirmed PR) according to RECIST v1.1 guidelines, as assessed 
by the local Investigator's review. 
Clinical Benefit Rate (CBR) [proportion of patients with confirmed CR, confirmed PR, or 
, as assessed by (i) 
the IRC and (ii) the local Investigator's review. 
Disease control rate (DCR; number of patients with confirmed CR, confirmed PR, or SD) 
according to RECIST v1.1 guidelines, as assessed by (i) the IRC and (ii) the local 
Investigator's review. 
Time to response, as assessed by (i) the IRC and (ii) the local Investigator's review. 
Duration of response, as assessed by (i) the IRC and (ii) the local Investigator's review. 
3.2.4. Secondary Safety Endpoints 
These will include: 
 
Type, frequency and severity of AEs (including serious adverse events [SAEs], adverse 
events of Special Interest [AESIs]). 
Laboratory abnormalities. 
Vital signs. 
Additionally, signs and symptoms of anaphylaxis will be captured and summarized in accordance 
with guidance provided by the Second Symposium on the Definition of Anaphylaxis. Evaluation 
of liver parameters will be made according to the evaluation of Drug-induced Serious 
Hepatotoxicity (eDISH) criteria; this requires a log-log plots of alanine aminotransferase 
(ALT)/aspartate aminotransferase (AST) vs total bilirubin to identify potential cases of concern, 
followed by time course plots of all the identified potential cases. 
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3.2.5. Exploratory Efficacy Endpoints 
Efficacy as measured by PFS, ORR and OS in each exploratory subgroup (Demographic 
and Baseline Characteristics, Disease History and Progression Status). 
Response, as assessed by iRECIST (2017) in those patients who continue treatment despite 
progression. 
EORTC-QLQ-C30 QoL change from baseline to the end of each treatment cycle. 
The FACT-B and EQ-5D change from baseline to the end of each treatment cycle. 
The following endpoints will be analyzed in a separate plan: 
Relationship between ORR, PFS, or OS and baseline biomarkers including ER status, PgR 
status or CXCR4 expression levels. 
 
Relationship between ORR, PFS, or OS and exploratory biomarkers (from tumor tissue or 
blood) including cytokines (e.g. IFN-gamma), immune cells profile, and ribonucleic acid 
(RNA) expression. 
 
Plasma concentration of balixafortide and potential metabolites (PK analysis set). 
 
3.3. Treatments 
Patients will be randomized as follows: 
 
3.3.1. Balixafortide + eribulin 
Patients will receive balixafortide + eribulin treatment. Balixafortide will be administered on Days 
 -day cycle. 
 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 
POL6326 
1 
2 
3 
treatment break 
8 
9 
10 
treatment break 
Eribulin 
2 
treatment break 
9 
treatment break 
 
3.3.2. Eribulin monotherapy 
Patients will receive eribulin monotherapy; Eribulin will be administered on Days 2 and 9 of each 
21-day cycle. 
 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 
Eribulin 
2 
treatment break 
9 
treatment break 
 
Balixafortide will be administered, at a dose of 5.5 mg/kg, intravenously over 2 hours ±10 min; 
however, the infusion time of balixafortide can be increased to a maximum of 3 hours at the 
discretion of the treating physician, for reasons of patient tolerability (i.e. to manage infusion 
related reactions). Eribulin should be administered intravenously as the ready to use solution at a 
dose of 1.4 mg/m2 over 2 to 5 minutes on Days 2 and 9 of each 21-day cycle. note: this dose is 
expressed as the salt, eribulin mesylate; however, in some countries this dose is expressed as the 
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base, equivalent to eribulin 1.23 mg/m2. Eribulin will be administered within 45 minutes after the 
end of balixafortide infusion. 
 
3.4. Dose Adjustment/Modifications 
 
3.4.1. Dose Modification Balixafortide 
In the event of significant treatment-related toxicity, balixafortide + eribulin dosing may be 
modified in two ways: 
Within a cycle: dosing interruption during a given treatment cycle until there is adequate 
recovery; 
Between cycles: administration of the next cycle may be delayed due to persistent toxicity. 
Patients that discontinue from balixafortide treatment due to treatment-related toxicity are to 
attend an EoT Visit within 7 days after discontinuation, the 30-day safety follow-up visit for 
assessments and recording of AEs and concomitant medications, and the Long-term Follow-up 
visits. 
 
3.4.2. Dose Modification Eribulin 
The dose of eribulin can be decreased or modified according to the US regulatory label for eribulin 
as detailed in the protocol. 
 
3.4.3. Dosing Delays or Interruptions 
Eribulin should not be given on Day 2 or Day 9, if any of the following occur: 
ANC <1000/mm3. 
Platelets <75000/mm3. 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 non- 
hematological toxicities. 
The Day 9 eribulin dose may also be delayed for a maximum of 1 week if toxicities: 
 
3.5. Do not resolve or improve to CTCAE Grade 
 16, omit the 
dose.Subscale Scoring for the FACT-B 
 
 
Resolve or improve to CTCAE Grade 
 16, administer the eribulin at a 
reduced dose and initiate the next cycle no sooner than 2 weeks later. 
If study treatment during a cycle is delayed for <14 days, then treatment can be resumed during 
that cycle. In these circumstances, the total duration of a cycle could potentially be extended up 
to 28 days. If study treatment during a cycle is delayed 
days, the treatment for that cycle 
is not resumed and the subsequent cycle is initiated as planned. If the next cycle cannot be initiated 
as planned, the patient should be discontinued from treatment unless discussed and agreed 
otherwise with the Sponsor. 
The doses of balixafortide on Days 1, 2 and 3 are interdependent with the eribulin dose on Day 2. 
Similarly, the doses of balixafortide on Days 8, 9 and 10 are interdependent with the eribulin dose 
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on Day 9. Therefore, if an eribulin dose is delayed by a few days during a cycle, then the 
adjunctive balixafortide doses must also be delayed accordingly during that cycle. 
Tumor assessments must continue to be performed according to the Study Schedule regardless of 
any dosing delay. 
 
4. General Statistical Considerations 
Summary statistics for continuous variables will include the mean, standard deviation, median, 
and range (minimum and maximum); the number of missing observations will also be displayed. 
The mean and median will be presented to one decimal place beyond which the data were 
captured. The standard deviation will be presented to two decimal places beyond which the data 
were captured. The minimum and maximum will be presented to the precision with which the 
data were captured. 
Categorical variables will be presented as frequency counts and percentages. A row or column 
and missing values. Percentages will be rounded to 1 decimal place and the percent will be 
suppressed when the count is zero. The denominator will be the number of patients in that dose 
schedule within the analysis set of interest unless otherwise noted. 
Time-to-event variables will be analyzed using the Kaplan-Meier (KM) method. The KM 
estimates for quartiles and the confidence interval (CI) for the median will be presented as 
described below. Kaplan-Meier curves will also be plotted. 
Time-to-event variables will be also analyzed by a Cox proportional hazards model. 
Data listings will be created to support each table and to present all data. Data listings will be 
presented by treatment arm and patient number. 
Although this is an open label trial, grouped evaluation of randomized treatment arms will be 
performed only for the pre-planned interim efficacy analyses and DSMB safety reviews as 
described in Section 8.0 of this document and in the DSMB charter. In order to protect the integrity 
of the trial and the robustness of the results, project team members, both Polyphor Ltd. and CRO 
personnel, will not evaluate, formally or informally, data grouped by randomized treatment arm 
as data are accruing over time. Procedures relating to the execution of pre-planned interim efficacy 
analyses and DSMB safety reviews are described in the DSMB Charter. 
Important study variables to be used in the analysis, defined as follows: 
Age 
 eCRF instead of the Date of Birth. 
Baseline: 
o For efficacy evaluations, the last available assessment before or at date of 
For PRO 
endpoints, baseline is the mean of the PROs taken at screening and at last visit 
before first treatment administration with no imputation done if any of them is 
missing. 
o For safety evaluations (such as laboratory and vital signs), the last available 
assessment before first study treat 
study treatment, 
the baseline will be the last assessment performed before randomization. 
o If patients have no value as defined above, the baseline result will be missing. 
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Study day: For post-treatment events, study day is calculated as (event/assessment date 
date of Day 1) + 1. For pre-treatment events, study day is calculated as event/assessment 
date 
date of Day 1. There is no study day zero. Day 1 is the date of Cycle 1 Day 1 for 
balixafortide + eribulin arm, while it is the date of Cycle 1 Day 2 - 1 for eribulin arm: 
o Balixafortide + eribulin arm: Cycle 1 Day 1. 
o Eribulin arm: (Cycle 1 Day 2) 1. 
Body Mass Index (BMI) (kg/m2) is defined as [Weight(kg)] / [Height(m)]2. 
Body Surface Area (BSA) (m2) is defined as 
. 
 
4.1. Sample Size 
The trial is powered for detecting superiority of balixafortide + eribulin versus eribulin 
monotherapy for the primary efficacy endpoint of PFS in the 3rd line+ population. 
In the trial, patients will be randomized in a 1:1 ratio to the two treatment arms stratified by line 
of therapy (2nd line versus 3rd line+), hormone receptor status (positive versus negative), prior 
treatment with CDK 4/6 inhibitor (received a CDK 4/6 inhibitor versus not received a CDK 4/6 
inhibitor) and visceral versus non-visceral disease. 
The sample size calculations are event-driven. In the 3rd line+ population, approximately 320 
patients are required in order that 286 PFS events occur within 24 months of randomizing the first 
patient. Patients who discontinue from the study will not be replaced. 
The sample size calculations were based on the following assumptions: 
Overall 1-sided type I error rate: 0.020; 
In the 3rd line+ population, a median PFS on eribulin monotherapy of 3.9 months vs 5.8 
months for balixafortide + eribulin to give a PFS hazard ratio 0.674; 
Power of 90%; 
Assuming a 12-month non-linear recruitment period ( =2; Carroll, 2009) and a minimum 
12-month follow-up period after the last patient is randomized. 
Further, assuming a median OS on eribulin monotherapy of 14.4 months vs 17.4 months 
for balixafortide + eribulin to give an OS hazard ratio 0.828, a total of 226 deaths are 
expected in the 3rd line+ population in the final analysis of OS, planned to take place 12 
months after the PFS analysis. Note, there is only one formal analysis of PFS to take place 
once 286 PFS events have accrued. No further formal analyses of PFS are planned. 
 
4.2. Randomization, Stratification, and Blinding 
This trial is an open-label, randomized, parallel, two-arm, multicenter, international Phase III trial. 
Patients will be randomized after the investigator has verified eligibility. 
Patients will be randomized in a 1:1 ratio to one of the following treatment regimens: 
Balixafortide + eribulin 
or 
Eribulin monotherapy 
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Patients will be stratified according to: 
Line of therapy (2nd line vs 3rd line+). 
HR receptor status (positive vs negative). 
Prior treatment with Cyclin-dependent kinase (CDK) 4/6 inhibitor (received a CDK 4/6 
inhibitor vs not received a CDK 4/6 inhibitor). 
Visceral vs non-visceral disease. 
For stratified analyses in the 3rd line+ population, the stratification factors (HR receptor status at 
randomization, prior CDK 4/6 inhibitor treatment and visceral disease) entered into the Interactive 
Response Technology (IRT) at the time of randomization will be used in analysis models. The 
randomization strata will be summarized by treatment arm for the Intention-to-treat (ITT) set, 
Line of therapy (only applicable in 2nd line population), HR receptor status, prior treatment with 
CDK 4/6 inhibitor (yes, no) and visceral disease (yes, no). Additionally, the exact line of therapy, 
as captured on the CRF, will also be summarized. 
The analyses by line of therapy will be done on data collected in IRT system and imported as such 
in eCRF. The exact number of lines of therapies is collected in eCRF and will be used to 
summarize any discrepancy with the stratification factor. 
The block size will be pre-specified and implemented in the IRT and will not be known to the 
Investigator. Polyphor Ltd. will determine the maximum number of patients that can be enrolled 
at each participating site and/or each geographic region. 
 
4.3. Analysis Set 
For the Food and Drug Administration (FDA) submission, the following analysis sets have been 
defined: Intent-to-Treat (3rd line+), Intent-to-Treat (3rd line+ confirmed), Per-Protocol (3rd line+ 
confirmed), Response Evaluable (3rd line+), Response Evaluable (3rd line+ confirmed), Patient 
Reported Outcome (3rd line+), Safety (3rd line+) in the 3rd line+ population. Note that the 3rd line+ 
population in these sets refers to those who were randomized as 3rd line+. 3rd line+ Confirmed 
refers to the subset of patients stratified as 3rd line+ who were confirmed as receiving the 
investigational medication as 3rd line of therapy or more in the eCRF data. 
The efficacy endpoints analysis will be conducted in the ITT sets: Intent-to-Treat (3rd line+) for 
PFS and OS and Response Evaluable (3rd line+) for ORR. The other additional sub-sets defined 
in this section Intent-to-Treat (3rd line+ Confirmed), Per-Protocol (3rd line+ Confirmed) and 
Response Evaluable (3rd line+ Confirmed) will be used for sensitivity analysis. 
In addition, the following analysis sets will be of interest for submissions to all regulators: 
Enrolled, Intent-to-Treat and Safety for the overall population. 
 
4.3.1. Enrolled Set 
Enrolled set is defined as all screened patients of the overall population who signed the informed 
consent. 
 
4.3.2. Intent-to-Treat Set 
The Intent-to-treat (ITT) set is defined as all randomized patients in the overall population. The 
co-primary endpoint PFS will be analyzed in this set if it is found to reach significance in the ITT 
(3rd line+) set as described in Section 8.3 and Figure 1. 
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4.3.3. Intent-to-Treat Set (3rd Line+) 
The Intent-to-treat (ITT) set (3rd line+) is defined as all randomized patients in the 3rd line+ 
population. The 3rd line+ population is defined in the study as patients allocated to the 3rd line+ 
randomization strata. Efficacy data in this analysis set will be summarized by randomized 
treatment. The co-primary endpoint PFS, key secondary efficacy endpoint OS and exploratory 
efficacy endpoints will be analyzed by the treatment arm to which they are randomized using ITT 
(3rd line+). 
4.3.4. Intent-to-Treat Set (3rd Line+ Confirmed) 
The ITT set (3rd line+ confirmed) includes only those ITT (3rd line+) patients confirmed as 
receiving the investigational medication as 3rd line of therapy or more, as per eCRF data. Note 
that this analysis set therefore excludes patients randomized in 3rd line+ but receiving the 
investigational medication as only the 1st line or 2nd line of therapy as per eCRF. 
A sensitivity analysis will be conducted on the co-primary endpoint PFS and the key secondary 
efficacy endpoint OS using the ITT set (3rd line+ Confirmed). Patients will be analyzed by the 
treatment arm to which they are randomized. 
 
4.3.5. Per-Protocol Set (3rd Line+ Confirmed) 
The Per-Protocol (PP) set (3rd line+ confirmed) is defined as a subset of the ITT set (3rd line+ 
confirmed), including only patients who took at least one dose of Eribulin and without any major 
protocol deviation that could affect the evaluability of the co-primary efficacy endpoints. Protocol 
deviations causing the exclusion of patient from PP set are listed in the Study Deviations Rules 
document. 
A sensitivity analysis will be conducted on the PFS and the key secondary efficacy endpoint OS 
using the PP set (3rd line+ confirmed). Patients will be analyzed by the treatment arm to which 
they are randomized. 
 
4.3.6. Response Evaluable Set (3rd Line+) 
The Response Evaluable (RE) set (3rd line+) will be used to evaluate disease response. The RE 
set (3rd line+) includes all randomized patients in the 3rd line+ population with measurable disease 
by RECIST v1.1 as determined by the Investigator at screening during the evaluation of breast 
cancer history. The co-primary endpoint analysis of ORR and other secondary endpoint analyses 
of CBR, duration of response, DCR and time of response will be conducted using the RE (3rd 
line+) set. Patients will be analyzed by the treatment arm to which they are randomized. 
 
4.3.7. Response Evaluable Set (3rd Line+ Confirmed) 
The Response Evaluable (RE) set (3rd line+ confirmed) is a subset of RE set (3rd line+) including 
only those patients confirmed as receiving the investigational medication as 3rd line of therapy or 
more, as per eCRF data. 
A sensitivity analysis will be conducted on the co-primary endpoint ORR using the RE set (3rd 
line+ confirmed) 
 
4.3.8. Patient Reported Outcome Set (3rd Line+) 
The Patient Reported Outcome (PRO) set (3rd line+) is defined as all randomized patients in the 
3rd line+ population where the patient has at least one post-baseline PRO value (e.g. EORTC 
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questionnaire, EQ-5D or FACT-B). Patients will be analyzed by the treatment arm to which they 
are randomized. 
 
4.3.9. Safety Set 
The Safety set consists of all randomized patients in the overall population who receive at least 
one dose (or partial dose) of study treatment (i.e. a subset of ITT).Patients will be analyzed by the 
treatment received, based on the first dose of study drug, to summarize the safety data overall. 
They will be included in the balixafortide + eribulin arm if they received at least one dose of 
balixafortide during the study. 
 
4.3.10. Safety Set (3rd Line+) 
The Safety set (3rd line+) consists of all patients from the ITT set (3rd line+) who receive at least 
one dose (or partial dose) of study treatment. Patients will be analyzed by the treatment received, 
based on the first dose of study drug. They will be included in the balixafortide + eribulin arm if 
they received at least one dose of balixafortide during the study. 
 
4.4. Handling of Missing or Partial Date Data 
Missing date data will be handled as follows: 
For prior cancer therapies and medical history of cancer, the study day corresponding to 
the start and stop date will be imputed prior to calculating duration of the therapy/history 
using the following rules: 
o For partially missing start dates, missing day of the month will be imputed as the 
first of the month and missing month will be imputed as January. No imputation 
will be done if the year is missing. 
o For partially missing stop dates, missing day of the month will be imputed as the 
last day of the month and missing month will be imputed as December and at least 
1 day after the start date of the therapy/history. Any imputed date occurring after 
the screening visit date will be imputed to the screening visit date. No imputation 
will be done if the year is missing. 
For prior radiotherapy and surgery, the relevant time to the initiation of the trial, etc. will 
be calculated using the recorded date of radiotherapy or date of procedure for surgery. The 
imputation rules described for prior cancer therapies will be applied to prior radiotherapy 
and surgery. 
For time since initial diagnosis to informed consent and time since diagnosis of locally 
recurrent or metastatic disease to informed consent, partial dates for initial diagnosis and 
diagnosis of metastatic disease, will be imputed as follows: 
o No imputation will be done if the year is missing. 
o If the year is before informed consent date, then missing days will be imputed as 
the first day of the month and missing months will be imputed as July. 
o If the year is the current year of informed consent date, then missing days will be 
imputed as the first day of the month and missing months will be imputed as 
January. 
For time since initial diagnosis to randomization, partial dates will be imputed as follows: 
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o No imputation will be done if the year is missing. 
o If the year is before randomization date, then missing days will be imputed as the 
first day of the month and missing months will be imputed as July. 
o If the year is the current year of randomization date, then missing days will be 
imputed as the first day of the month and missing months will be imputed as 
January. 
For Prior or Concomitant Medication: Partial start or stop dates (where UN and UNK 
indicate unknown day and month respectively) will be imputed as follows: 
o Start dates: 
UN-MMM-YYYY: Impute missing day as 01, so that CMs are assigned to 
DD-UNK-YYYY/UN-UNK-YYYY: If the year is before the year of first dose 
of study treatment, assume 01-JUL-YYYY of the collected year. If the year is 
after the year of first dose of study treatment, assume 01-JAN-YYYY of the 
collected year. If the year is the same as the year of first dose of study treatment 
and the stop date (after any imputation) is missing or is on or after the first dose 
of study treatment, then assume 01-JAN-YYYY, so that CMs are assigned to 
prior and concomitant. If the year is the same as the year of first dose of study 
treatment and the stop date (after any imputation) is prior to the first dose of 
study treatment, then assume the stop date for the start date. 
o Stop dates: 
UN-MMM-YYYY: Assume the last day of the month. 
DD-UNK-YYYY/UN-UNK-YYYY: Assume 31-DEC-YYYY. 
In case of the death/study termination of the patients and the imputed stop date 
is after the date of death/study termination, the stop date will be imputed as the 
date of death/date of study termination. 
Completely missing dates will not be imputed. 
For Post Anti-Cancer Therapies: Rules are as per concomitant medications above except 
when the imputed start date is earlier than the date of last dosing date, then the start date 
will be imputed as the date of last dosing date of study treatment + 1. 
For Adverse Events (missing month is not expected; missing day is allowed): Partial start 
or stop dates will be imputed as follows: 
o Partial start dates (where UN indicates unknown day): 
UN-MMM-YYYY: If the month and year are different from the month and 
year of the first dose of study treatment, or the year is the same as the year of 
the first dose of study treatment, but the month is different, assume 01-MMM- 
YYYY. If the month and year are the same as the first dose of study treatment 
month and year and the end date (after any imputation) is missing or is on or 
after the first dose of study treatment, then assume the date of the first dose of 
study treatment. If the month and year are the same as the first dose of study 
treatment month and year and the end date (after any imputation) is prior to the 
first dose of study treatment, then assume 01-MMM-YYYY. 
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o Partial end dates (where UN indicates unknown day): 
UN-MMM-YYYY: Assume the last day of the month. 
In case of the death/study termination of the patients and the imputed end date 
is after the date of death/study termination, the end date will be imputed as the 
date of death/date of study termination. 
For OS with partial death date: 
o Every effort will be made to collect accurate death date. In case that the day is 
missing, the later date of the following will be used to calculate time to death: 
first day of the month 01-MMM-YYYY, or 
last visit date + 1, or 
last known alive date + 1. 
o If day and month are both missing, the later date of 1st January of that year 01- 
JAN-YYYY, last visit date + 1, or last known alive date + 1 will be assumed when 
calculating time to death. 
o If death date is completely missing then the later of last visit date + 1, or last known 
alive date + 1 will be assumed when calculating time to death. 
Handling of missing data for analysis of PFS and QoL are described in the statistical analysis 
sections 8.1.1, 8.5.1 and 8.5.2. 
 
4.5. Mapping of Unscheduled visits 
All planned assessments will be reported without any remapping. 
Missing scheduled assessments will not be replaced by unscheduled assessments. 
 
4.6. COVID-19 Impact 
Coronavirus (COVID-19) pandemic of 2019-20 poses risks to the safety of subjects enrolled in 
clinical trials, and the availability and interpretability of data from those trials. The FDA suggests 
sensitivity analyses to examine differences in baseline characteristics and post-baseline events 
between the originally enrolled participants and any additional participants. 
The European Medicines Agency suggests to conduct risk assessment, primarily using aggregate 
blinded data, of the impact of COVID-19 on trial integrity and interpretability. This should 
consider implications on recruitment, loss of patients during the trial, ability to record data and 
ability to interpret the treatment effect (considering impacts on both trial participants and clinical 
trial conduct). 
Any analysis at this stage would be premature considering data collection regarding COVID-19 
is ongoing. A separate meeting will be held between Polyphor and PPD to evaluate the amount of 
data affected by COVID-19. 
Potential follow-up considerations based on the risk assessment may include the following: 
Validation of outcomes that were measured differently before and after start of the 
pandemic; 
The need to adjust the trial sample size; 
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Handling sources of bias such as missing values and newly identified intercurrent events 
(e.g. deaths or serious illness, missed or delayed doses due to missed visits, 
Discontinuation of study treatment due to logistical issues, Extension of treatment duration 
due to delayed end-of-study visit, Use of additional prohibited medications); 
 
re-start the trial. 
In case the study conduct of a significant amount of patients will be affected by COVID-19, a 
sensitivity analysis will be proposed by PPD and agreed with Polyphor. 
 
5. Patient Disposition 
 
5.1. Disposition 
A summary of patient disposition will display the number of patients who were randomized and 
who comprised each analysis set by treatment arm for the Enrolled set. In addition, the number of 
patients with status of completed, ongoing and discontinued study; reason for discontinuation 
from study will be summarized for the ITT (3rd line+) set. Also, the number of patients who 
discontinued from study treatment, overall and by reason; and the number of deaths and reason 
will be presented. The number of patients recruited by geographical region [USA, Europe, Asia 
and Latin America] will also be summarized for the ITT (3rd line+) set. Disposition data, including 
analysis sets to/from which patients are included/excluded, will be presented in a data listing. 
The three randomization stratification factors relevant to the 3rd line+ population (HR receptor 
status, CDK 4/6 inhibitor treatment, and visceral disease) will be listed and summarized as 
recorded in the IRT system by treatment arm as randomized. 
 
5.2. Protocol Deviations 
The definition of protocol deviations will be made by the joint Polyphor/PPD trial team (clinical, 
medical and statisticians). The identification of protocol deviations will be conducted by clinical 
team. 
All significant protocol deviations will be summarized by treatment arm, site and overall, 
importance (major/minor) and activity subtype for the ITT (3rd line+) set. 
All protocol deviations will be listed. 
 
5.3. Missed Visits due to COVID-19 
Information about missed visits due to COVID-19 will be recorded on a dedicated page in eCRF. 
All information collected on this page will be presented in listing for ITT (3rd line+) set. 
Treatment discontinuation and study termination due to COVID-19 will be reported in listing of 
patient disposition. 
 
6. Demographics and Baseline Characteristics 
The following baseline data will be summarized and listed in separate tables for the ITT (3rd line+) 
set: Age (years), age group (<65yr, >=65yr), sex, race, ethnicity, fertility status, birth control 
method, height (cm), weight (kg), BSA (m2), BMI (kg/m2), systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), line of therapy(as collected in eCRF), ECOG performance 
status, smoking history (yes, no) and tobacco usage (current, previous) for smokers. All 
demographic data will be presented in a listing. 
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6.1. Medical History 
 
6.1.1. General Medical History 
Medical conditions collected at screening will be mapped by the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA) and will be summarized by system organ class 
(SOC) and preferred term (PT) by treatment arm for the corresponding ITT (3rd line+) set. For 
summary tables, a patient will be counted only once per SOC and PT. All data will also be 
presented in a listing. 
General Medical History will include significant medical conditions including other cancer 
history, prior surgeries and concurrent illnesses. 
 
6.1.2. Breast Cancer History 
Medical history of breast cancer will be summarized for the corresponding ITT (3rd line+) set. 
Breast Cancer History will include time since initial diagnosis of breast cancer (years), time since 
diagnosis of locally recurrent or metastatic disease (years), stage at initial diagnosis, stage at study 
entry, date of last tumor progression before study entry, histologic subtype, ER status, PgR status, 
HER2 status (FISH, CISH, IHC, other), site of disease, tumor marker status and Triple-Negative 
Breast Cancer (TNBC) subtype. For tissue profiling, if multiple assessments of breast cancer 
history data exist, only the last tumor assessment before randomization will be summarized. Time 
since initial diagnosis and since metastatic disease will be derived as follows: 
Time since initial diagnosis (years): (Date informed consent signed Date of initial 
diagnosis) / 365.25. 
Time since diagnosis of locally recurrent or metastatic disease (years): (Date of informed 
consent date Date of diagnosis of locally recurrent or metastatic disease) / 365.25. 
See Section 4.4 for data handling rules for partial initial diagnosis and diagnosis of locally 
recurrent / metastatic disease dates. 
All breast cancer data will also be presented in a listing. 
 
6.1.3. Prior Anti-Cancer Therapy 
The number and percent of patients receiving prior anthracycline and/or a taxane will be 
summarized. The number of prior hormonal therapies, immunotherapies, targeted therapies, 
cytotoxic chemotherapy agents for breast cancer, neoadjuvant agents, adjuvant agents, cytotoxic 
agents for locally recurrent and metastatic disease, will be presented based on prior cancer 
therapies reported on eCRFs and summarized for the corresponding ITT (3rd line+) set. 
Duration of prior anthracycline and/or taxane use will be summarized descriptively. 
Prior systemic cancer/oncology therapies will be tabulated for the corresponding ITT (3rd line+) 
set using the World Health Organization Drug Dictionary Enhanced (WHO-DDE) and 
Anatomical, Therapeutic, or Chemical (ATC) level-4 classifications and preferred term. If the 
ATC level-4 classification is missing, the next non-missing lower level of classification will be 
used (level 3). If a patient reports the same medication multiple times, then the frequency of that 
medication will be incremented by only one in the applicable arm. If a patient reports multiple 
medications within the same ATC level-4 classification, then the frequency of that ATC level-4 
classification will be incremented by only one in the applicable arm. Percentages will be 
calculated using the number of patients in the corresponding ITT (3rd line+) set. The summary 
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table will be ordered by descending incidence of ATC class and by descending incidence of 
preferred drug name within each ATC class for all patients. 
Data listings for prior systemic cancer/oncology therapies will include dose, unit, dose regimen 
frequency, best response to cancer therapy, and reason for discontinuation (toxicity, other or 
progressive disease). The study day corresponding to the starting and stopping date of the regimen 
will be calculated for display in the data listing. 
The duration of last chemotherapy line before entering in the study will be summarized by 
treatment arm. The duration (months) is calculated by (Cancer Therapy End Date Cancer 
Therapy Start Date + 1) / 30.4375. Any missing or partial date will be imputed according to section 
4.4. 
 
6.1.4. Previous Radiotherapy and Surgical History 
Previous radiotherapy and surgical history related to breast cancer will be listed for ITT (3rd line+) 
set. 
Surgical history related to breast cancer and percentage of patients receiving prior radiotherapy 
will be summarized for the ITT (3rd line+) set. 
6.2. Inclusion and Exclusion Criteria 
 (3rd line+) set. 
7. Treatments and Medications 
 
7.1. Prior and Concomitant Medications 
Prior and concomitant medications will be recorded on the eCRF and coded to as per ATC and 
preferred drug name using the prevailing version of the WHO-DDE dictionary. The summary 
tables will be ordered by descending incidence of ATC class and by descending incidence of 
preferred drug name within each ATC class for all patients. 
Concomitant medications are defined as medications with a start date on or after the date of the 
first dose in Cycle 1 up to 30 days following the last dose of study treatment in the study; it will 
also include medications initiated prior to the date of the first dose of study treatment and 
continued during treatment. 
Concomitant medications will be summarized by treatment for the Safety set by WHO-DDE ATC 
classification and preferred term. If the ATC level-2 classification is missing, the next non- 
missing lower level of classification will be used (level 1). If a patient reports the same medication 
multiple times, then that medication will be counted only once. If a patient reports multiple 
medications within the same ATC level-2 classification, then the frequency for that ATC level-2 
classification will be incremented by only one. Percentages will be calculated using the total 
number of patients in the Safety set. 
Prior medications are defined as medications taken from 28 days prior to the first dose of study 
treatment in Cycle 1. Prior medications will be summarized similarly to concomitant medications 
for the ITT (3rd line+) set. Percentages will be calculated using the total number of patients in the 
ITT (3rd line+) set. 
Prior and concomitant medications will be presented in a data listing. 
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7.2. Post Anti-Cancer Therapy 
Post anti-cancer therapies (therapies applied after study treatment discontinuation for subjects that 
are continuing in the study for the FU phase) as reported in Post Anti-Cancer Therapy eCRF page 
will be summarized for the corresponding ITT (3rd line+) set, using the WHO-DDE and ATC 
level-4 classifications and preferred term. The number and percent of patients who took at least 
one post anti-cancer therapy will be calculated and presented by treatment arm, ATC level-4 
classifications, and preferred term. 
 
7.3. Study Treatments 
Information about study treatments balixafortide and eribulin are provided in Section 3.3. 
In the eCRF weight of eribulin is collected in both base and salt, this should be converted to salt 
by dividing by a factor of 0.88366. 
 
Conversion factor is derived per weight as base and weight as salt: 
Weight as base / Weight as salt = 826.0 / 729.9 = 0.88366. 
7.3.1. Extent of Exposure 
Overall exposure to study treatment will be summarized for the Safety set. 
The following exposure variables will be derived: 
Study treatment duration (days): date of last dose 
date of first dose + 1. 
Number of cycles: Total number of complete or partial treatment cycles the patient 
received. 
Total cumulative dose (mg): The sum of actual doses (mg) received across all cycles. 
Average Duration of infusion: The mean duration of infusion across all cycles for each 
patient. The duration of infusion will be calculated as; completion time of infusion start 
time of infusion; where infusions have been paused, the duration of the infusion will be 
computed as the sum of the start/stop and interrupted/restarted times as captured in the 
eCRF. 
Total cumulative dose and average duration of infusion will be derived per drug. 
 
7.3.2. Treatment Compliance and Modifications 
The number of patients with dose reduction, dose interruption, missed dose, and dose delay will 
be summarized along with their reason. A dose interruption is defined as a dose stopped at least 
one time while being administered. A dose is missed when the administration at site does not 
occur. A dose delay occurs when the patient receives the treatment not as per scheduled date. All 
summaries will be performed for each cycle and for all cycles combined. 
The following parameters will be calculated for balixafortide: 
Dose intensity (mg/kg/cycle): [Sum of actual doses received (mg/kg) across all cycles]/ 
(number of cycles received). 
Expected dose intensity (mg/kg/cycle): initial planned dose (5.5 mg/kg) [i.e. dose for each 
injection] × 6. 
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Relative dose intensity (%): ((Dose intensity) / (expected dose intensity)) × 100. 
Average dose per infusion (mg/kg/infusion): [Sum of actual dose received (mg/kg) across 
all cycles] / (number of infusions received). 
The following parameters will be calculated for eribulin: 
Dose intensity (mg/m2/cycle): [Sum of actual doses received (mg/m2 salt) across all 
cycles] / (number of cycles received). 
Expected dose intensity (mg/m2/cycle) = initial planned dose (mg/m2 )[i.e. dose for each 
injection] × 2 
Relative dose intensity (%): ((Dose intensity) / (expected dose intensity)) × 100. 
Average dose per infusion (mg/m2/infusion): [Sum of actual doses received (mg/m2) 
across all cycles] / (number of infusions received). 
 
8. Efficacy Analysis 
Analysis of efficacy endpoints will be performed using the ITT set (3rd line+) unless otherwise 
noted. 
As described in Section 3.1, a retrospective review of radiographic images and relevant clinical 
information (surgical history) collected on-study to verify the protocol defined endpoints of 
disease response and progression, as assessed by the Investigator will be performed. The IRC will 
be blind to treatment and will be able to provide consistent assessment over all the sites. Based on 
these blinded, central review of CT/MRI scans performed every 6 weeks (±7 days) during the first 
year, and then performed every 12 weeks (±7 days), until PD is documented by RECIST v1.1; the 
patients will be evaluated for Complete Response (CR), Partial Response (PR), Stable Disease 
(SD), Progressive Disease (PD) or Not Evaluable (NE). 
 
8.1. Co-Primary Efficacy Endpoint 
The sequence of testing efficacy and alpha recycling is explained in Section 8.3 and Figure 1. 
 
8.1.1. Progression-Free Survival 
PFS, as assessed by the IRC, is a co-primary efficacy endpoint in the 3rd line+ population. The 
RECIST v1.1 guidelines will be used to determine disease progression. The alpha allocation will 
be 0.040 2-sided. From the date of randomization, patients will be evaluated for PD based on 
blinded, central review of CT/MRI scans as described in Section 8. Patients who discontinue study 
treatment prior to PD will undergo repeat CT/MRI scans and tumor response assessments every 
8 weeks (±7 days) for the first year post randomization and 12 weeks (±7 days) after the first year 
post randomization, regardless of regimen, until confirmed PD is documented, death occurs, 
patient is lost to follow-up, or the patient withdraws consent (whichever occurs first). 
Date of Progression will be the date assessed by the IRC. 
PFS is defined as the time from the date of randomization to the earliest evidence of documented 
PD or death from any cause. Patients who are alive without documented PD or are either lost to 
follow-up or withdrew consent, will be censored at the date of last tumor assessment without 
disease progression. 
The duration of PFS will be calculated as follows: 
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For patients who have PD or died, Duration of PFS = Date of death/PD 
Date of 
randomization + 1 day; 
For patients who are alive without documented PD, Duration of PFS = Date of last tumor 
assessment (where response is not missing or unable to evaluate) Date of randomization 
+ 1 day. 
 
Table 1 below specifies the date of disease progression or censoring rules that will be carried out 
for the PFS analysis on the ITT (3rd line+) set: 
 
Table 1 - Date of Progression or Censoring for Progression-free Survival 
 
Situation 
Date of Disease Progression or Censoring 
Outcome 
No post-baseline assessments for tumor response 
and no death within first two tumor assessments 
Date of randomization 
Censored 
Disease progression or death after two or more 
consecutive missed tumor response assessments 
Date of last scan for tumor assessment showing no 
evidence of disease progression that is before the first 
missed visit 
Censored 
Not known to have progressed or died according 
to data in the database as of data-cut-off 
Date of last scan for tumor assessment showing no 
evidence of disease progression 
Censored 
Disease progression reported on multiple 
response assessments 
Earliest Date of Progression 
Progressed 
Disease progression or death after one missed 
tumor response assessment 
Earliest Date of Progression 
Progressed 
Death without PD 
Date of death 
Progressed 
Starting anti-cancer therapy prior to observing PD 
or in absence of PD 
Date of last scan for tumor assessment showing no 
evidence of disease progression prior to start date of 
the anti-cancer therapy 
Censored 
 
8.1.2. Objective Response Rate 
Objective response rate (ORR), defined as the proportion of patients with a confirmed complete 
response (CR) or a confirmed partial response (PR) according to RECIST v1.1 based upon the 
best response assessed, is a co-primary efficacy endpoint. The alpha allocation will be 0.001 2- 
sided. As described in section 8, patients will be evaluated for tumor response according to 
RECIST v1.1 for confirmed CR, confirmed PR, SD, or PD based on blinded, central review of 
CT/MRI scans. Response will be based on the IRC assessment with a supportive analysis based 
on the local Investigator's review. Following initial documentation of an objective response, a 
confirmatory CT/MRI scan will be performed at least 4 weeks later. Results based upon scans 
performed after start of new anti-cancer therapy will be excluded for analysis derivations. 
For the secondary Efficacy Endpoints, the confirmed responses (best responses) determined from 
Overall responses bas
 eCRF and will 
be derived from the algorithm described in Appendix 14.5. 
These data from the CT/MRI scans will be presented in listings; listings for tumor assessment 
(target, non-target lesions, new lesions, sum of diameters, assessment of disease based on MRI 
and bone scan). Furthermore, the tumor assessments by the IRC will also be listed. 
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8.1.3. Primary Analysis 
Progression-Free Survival 
PFS, as assessed by the IRC, will be analyzed via a Cox proportional hazards model on the ITT 
(3rd line+) set and if found to be significant also in the ITT set as described in section 14.2. 
Analysis of the ITT (3rd line+ confirmed) and PP (3rd line+ confirmed) sets is added as sensitivity 
and is not part of the alpha-control for this study. The analyses will be stratified for randomization 
stratification factors (excluding lines of therapy in the 3rd line+ sets) and a fixed effect term will 
be included for treatment arm. 
The hazard ratio (balixafortide + eribulin vs eribulin monotherapy) will be estimated from the 
model along with the associated 96% CI and 2-sided p-value. 
If PFS in the 3rd line+ population is met at the allocated alpha level, PFS in the overall population 
will also be formally tested at the same alpha level. (i.e. 0.040 2-sided). 
The summary of reasons for PFS censoring will display the following categories (based on the 
end of treatment eCRF page, the study termination page, the survival follow-up eCRF page and 
relevant derivations of tumor assessments): 
Ongoing without event 
Lost to follow-up 
Withdrew consent 
Adequate assessment no longer available (No post-baseline assessments) 
New anti-cancer therapy added 
Event documented after two or more missing tumor assessments 
As the Cox proportional hazards model assumes odds are proportional, a supportive analysis for 
PFS, as assessed by the IRC, will be conducted for the ITT (3rd line+) set using a stratified log- 
rank test which does not hold this same assumption; strata will be the randomization stratification 
factors for 3rd line+ population excluding line of therapy (see Section 4.2 for further details). The 
2-sided p-value will be extracted from the stratified log-rank test and presented alongside the 
results of the Cox proportional hazards model analysis. 
The number of patients experiencing events and the number of censored patients will be 
summarized by randomized treatment arm with reasons for an event/censoring. The median 
survival times will be estimated by the Kaplan-Meier method and presented along with their 
corresponding 95% CI. The 25th percentile and 75th percentile for the survival times along with 
the corresponding 95% CI for the percentiles will also be displayed, CI will be calculated using 
method of Brookmeyer and Crowley (1982). Additionally, PFS probabilities at fixed time points 
i.e. 3, 6, 9, 12, 15 months will be derived from the Kaplan-Meier estimates with 95% confidence 
intervals, CI will be calculated using the Greenwood formula. The time points will be displayed 
based on the data availability. 
Corresponding plots of Kaplan-Meier curves by treatment arm will also be presented. The plots 
will display the number of patients at risk every 3 months. Alongside this the PFS data will be 
presented in a listing by treatment arm. 
Objective Response Rate 
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The ORR, defined from the best response as assessed by the IRC, will be analyzed by an exact 
logistic regression, stratified for randomization stratification factors excluding line of therapy (see 
Section 4.2 for further details). The odds ratio will be estimated from the model along with the 
associated 99.9% CI (0.001 alpha) and 2-sided p-value. Exact Clopper-Pearson 2-sided 95% 
confidence limits will be calculated for the proportion of patients with objective response in each 
arm. 
ORR analyses will be performed for the RE (3rd line+) set and RE (3rd line+ Confirmed) set. 
Analysis of the RE (3rd line+ Confirmed) set is added as sensitivity and is not part of the alpha- 
control for this study. In addition to presenting ORR, the best response as assessed by the IRC 
using response categories CR, PR, SD, PD and NE will be summarized. The number and 
percentage of patients in each response category will be presented by treatment arm. Patients who 
do not have any post-baseline tumor assessment will be counted under the category NE. SD 
requires at least one post-baseline scan performed at minimum of six (6) weeks (42 days) +/- seven 
(7) days, for a minimum time on-study of thirty-five (35) days or later. Patients who did not have 
any post baseline scans for the 6-week assessment or later and also do not have a documented PD 
will be counted as NE. 
 
8.1.3.1. 
Sensitivity Analysis for PFS 
A sensitivity analysis will be conducted for PFS, as assessed by the IRC on the ITT (3rd line+) set. 
The calculation of PFS is the same as described in section 8.1.1 where patients will not be censored 
at the start of a new anti-cancer therapy prior to observing documented PD. The same statistical 
analysis methods: Kaplan-Meier analysis, Cox proportional hazards model and supportive 
analysis using a stratified log-rank test will be used to estimate the effect of treatment irrespective 
of starting a new anti-cancer therapy. 
 
8.2. Key Secondary Efficacy Endpoint Analysis 
OS is the key secondary endpoint. The alpha allocation will be between 0.001 and 0.002 2-sided 
at the interim and between 0.008 and 0.050 at the final analysis depending on the results of 
previous analyses PFS and ORR analyses as illustrated in the flow diagram of section 14.2. 
OS defined as the time from the date of randomization to death from any cause will be assessed 
in the ITT (3rd line+) set. The ITT (3rd line+ confirmed) and PP (3rd line+ confirmed) sets will 
also be analyzed as sensitivity. Patients will be followed until their date of death, lost to follow- 
up, withdrawal of consent, or end of study. 
Patients who are lost to follow-up or are not known to have died at the time of data-cut-off for 
analysis will be censored at later of last visit date, or last known alive date. 
Patients who do not have any follow up since randomization will be censored at the date of 
randomization. 
The duration of overall survival will be calculated for all randomized patients as follows: 
For patients who have died: Duration of overall survival = Date of death Date of 
randomization + 1 day; 
For patients who are lost-to-follow-up or not known to have died: Duration of overall 
survival = Later of Date of last visit date, last date known to be alive Date of 
randomization + 1 day; 
See section 4.4 for details on how to handle partial death date. 
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OS will be analyzed using the same Cox proportional hazards model as PFS. The CI coverage for 
OS at the planned interim and at the final analysis will be determined by the allocated alpha level. 
A supportive analysis for OS will be conducted using a stratified log rank test for the ITT (3rd 
line+) set again as per the analysis of PFS; strata will be the randomization stratification factors 
as described in Section 8.1.3 for PFS. 
The OS proportion at 6, 12 and 18 months, including 95% CIs, will also be presented. 
 
8.3. Timing of Analyses of Primary and Key Secondary Efficacy Endpoints and Type I 
Error control 
In the 3rd line+ population co-primary efficacy endpoints are ORR and PFS; the key secondary 
efficacy endpoint is OS. A formal analysis of ORR is planned once all 3rd line+ patients have been 
randomized and followed for a minimum of 6 months. The formal analysis of PFS will take place 
once 286 PFS events have accrued, being expected when all randomized patients in the 3rd line+ 
strata have been followed for a minimum of 12 months. The alpha allocation for the PFS analysis 
will be 0.040 2-sided; if the PFS in the 3rd line+ population meets the allocated alpha level, PFS 
in the overall population will also be formally tested at the same alpha level; further, at the time 
of the PFS analysis an interim analysis of OS will be performed with an alpha allocation of 0.001 
to 0.002 2-sided, depending on the result of the previous ORR analysis. The final analysis of OS 
will take place once all randomized patients have been followed for a minimum of 24 months at 
which time 226 events are expected. The alpha allocation for this analysis will be between 0.008 
and 0.05 2-sided depending on the results of previous analyses. Thus, there will be 4 formal 
efficacy analyses in the 3rd line+ population (ORR, PFS, interim OS and final OS). If PFS is met 
in the 3rd line+ population, PFS analysis will be performed in the overall population. 
Consequently, there will be a total of 5 formal efficacy analyses. The overall Type I error rate will 
be controlled at 0.05 across these formal analyses by means of alpha allocation and recycling as 
described in Figure 1 in Appendix 14.2. 
 
8.4. Other Secondary Endpoints 
Other secondary endpoints are PFS according to RECIST v1.1 guidelines, as assessed by the local 
Investigator's review, and ORR (confirmed CR + confirmed PR) according to RECIST v1.1 
guidelines, as assessed by the local Investigator's review. Additionally CBR, DCR, time to 
response and duration of response will be analyzed. These analyses will be supportive in nature 
and, hence, will not be subject to Type I error control. Statistical tests will be 2-sided with a 
nominal Type I error rate of 0.05. 
PFS and ORR as assessed by investigator, will be analyzed as described in Section 8.1.3 for the 
ITT (3rd line+) set. Date of Progression will be the date assessed by the investigator. 
CBR and DCR will be analyzed in ITT (3rd line+) set and RE (3rd line+) set. Time to response and 
duration of response will be analyzed only in RE (3rd line+) set. These analyses will be performed 
for parameters defined from the best responses as assessed by (i) the IRC and (ii) the local 
Investigator's review. 
 
8.4.1. PFS Assessed by 
 
PFS, as 
, will be analyzed as described in section 8.1.3. 
The date of assessment 
 
 
according to RECIST v 
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8.4.2. 
 
ORR 
, will be analyzed as described in section 8.1.3. It 
will be defined as the proportion of patients with a confirmed CR or a confirmed PR according to 
RECIST v1.1 based upon the best response assessed
. The 
confirmed responses (best responses) are not entered in the eCRF, the algorithm for the best 
response determination according to RECIST v1.1 guidelines, as assessed by the local 
Investigator's review, can be found in Appendix 14.5. 
The Date of First Response is defined as the time point response (TPR) date when the criteria for 
CR or PR were first met, whichever status is recorded first, for subjects whose confirmed response 
(Best Response) is either a CR or a PR. The Date of First Response may or may not be the same 
as the Date of Best Response. 
 
8.4.3. Clinical Benefit Rate 
Clinical benefit rate (CBR) is defined as the proportion of patients with a confirmed CR, 
The CBR, as assessed according to RECIST v1.1 guidelines by the IRC, will be analyzed for RE 
(3rd line+) and ITT (3rd line+) analysis sets using an exact logistic regression as described for ORR 
in Section 8.1.3. 
 
RE (3rd line+) and ITT (3rd line+) analysis sets using an exact logistic regression as described for 
ORR in Section 8.1.3. 
 
8.4.4. Disease Control Rate 
Disease control rate (DCR) is defined as the proportion of patients with a confirmed CR, 
confirmed PR, or SD of any duration. Patients with SD of any duration as the best response will 
be considered for this analysis and not only patients with SD of confirmed best response. 
The DCR, as assessed by IRC, will be analyzed for RE (3rd line+) and ITT (3rd line+) analysis sets 
using an exact logistic regression as described for ORR in Section 8.1.3 
 
RE (3rd line+) and ITT (3rd line+) analysis sets using an exact logistic regression as described for 
ORR in Section 8.1.3. 
 
8.4.5. Time to Response 
Time to response is defined as the time from randomization to the first confirmed CR or PR as 
assessed by IRC 
. Time to response will be analyzed for the RE 
(3rd line+) set via Cox proportional hazards modelling with a fixed effect term for treatment arm 
and stratified by stratification factors. The hazard ratio (balixafortide + eribulin vs eribulin 
monotherapy) will be estimated from the model along with the associated 95% CI and 2-sided p-
value. The hazard ratio is interpreted, in the context of response, as the odds a patient will 
respond faster with the combination therapy as compared to eribulin monotherapy so a value > 1 
shows the addition of balixafortide to be beneficial. 
The data will also be displayed using Kaplan-Meier curves; median time to response and the 95% 
CIs will be estimated as described for PFS in Section 8.1.3. 
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 RE (3rd 
line+) set as described for PFS in Section 8.1.3. 
No censoring rule will apply since Time to Response will only be analyzed for patients achieving 
a confirmed response CR or PR. 
This data will be presented 
 review. 
 
8.4.6. Duration of Response 
Duration of response is defined as the time from first confirmed CR or PR until the earliest 
evidence of disease progression or death from any cause, as assessed by IRC review. The 
algorithm for calculation of Date of Progression and censoring rules will be the same as defined 
in the analysis for PFS, as described for PFS in Section 8.1.3. 
Duration of response will be analyzed for the RE (3rd line+) set via Cox proportional hazards 
model with a fixed effect term for treatment arm and stratified by stratification factors. The hazard 
ratio (balixafortide + eribulin vs eribulin monotherapy) will be estimated from the model along 
with the associated 95% CI and 2-sided p-value. The data will also be displayed using Kaplan- 
Meier curves; median duration of response and the 95% CIs will be estimated as described for 
PFS in Section 8.1.3. 
Since duration of response is assessed in responding patients only, the comparison is biased and 
could be misleading if the ORR differs moderately between the treatment arms. Hence, a 
supportive analysis will be performed based on the expected duration of response as per Ellis et 
al (2008) as this analysis includes all randomized patients, including those who did not respond, 
and so provides a valid comparison of the treatment arms. The expected duration of response is a 
product of the estimated fraction of patients with a response (ORR) and the mean duration of 
response in responding patients. 
 
(3rd line+) set as described for PFS in Section 8.1.3. 
This data will be presented 
8.5. Exploratory Efficacy Endpoints 
Analysis of the other exploratory efficacy endpoints will not be subject to Type I error control. 
Statistical tests will be 2-sided with a nominal type I error rate of 0.05. Exploratory subgroup 
efficacy analyses of PFS, ORR and OS will be performed to qualitatively assess if the overall 
treatment effect is broadly consistent between clinically important subgroups. 
The following subgroups will be analyzed for the ITT (3rd line+) set and for the RE (3rd line+) set 
as described below: 
o Age category (<65yr vs 
65yr) 
o Race (White, Black, Asian) 
o Visceral disease at baseline (Yes versus No) 
o Number of sites of disease involved 
 versus > 2) 
o ECOG status at baseline (0 versus 1 versus 2) 
o Prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitor (received a CDK 
4/6 inhibitor vs not received a CDK 4/6 inhibitor) only for HR+ patients 
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o Prior capecitabine (Yes versus No) 
o Prior immune therapy (Yes versus No) only for TNBC patients 
o Number of prior lines of therapy ( 2, 3, 4) 
o Receptor status [TNBC versus HR+] 
o Estrogen receptor status (Positive versus Negative) 
o Progesterone receptor status (Positive versus Negative) 
o Metastasis in liver (Yes versus No) 
o Metastasis in lung (Yes versus No) 
o Time from initial diagnosis to randomization (<2 years versus 
2 years) 
o Region (USA, Europe, Asia and Latin America) 
The following subgroups will be analyzed for the ITT (3rd line+ Confirmed) set and for the RE 
(3rd line+ Confirmed) set as described below: 
o Receptor status [TNBC versus HR+] 
o Prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitor (received a CDK 
4/6 inhibitor vs not received a CDK 4/6 inhibitor) only for HR+ patients 
o Visceral versus non-visceral disease 
 
Subgroups analyses for PFS, as assessed by IRC, and OS will be achieved by use of a Cox 
proportional hazards model with fixed effect terms for treatment arm, the subgroup as a class 
variable and treatment arm by subgroup interaction. The p-value for the interaction will be used 
as guide to the statistical plausibility of a true difference in the treatment effect between levels of 
the subgroup; an interaction p-value <0.05 will be suggestive of a true difference in the treatment 
effect between levels of the subgroup. The hazard ratio (balixafortide + eribulin vs eribulin 
monotherapy) together with its 95% CI and 2-sided p-value will be presented for each level of the 
subgroup. The hazard ratios and associated 95% CI will be displayed in a forest plot along with 
the interaction p-value. Subgroup analyses above may not be performed if the sample size is too 
small to provide accurate estimate. 
Subgroup analyses for ORR will be achieved via an exact logistic regression, including an 
interaction term for treatment arm by subgroup interaction. The odds ratio will be estimated from 
the model along with the associated 95% CI and 2-sided p-value, additionally the p-value for the 
interaction term will be presented on the summary table. Exact Clopper-Pearson 2-sided 95% 
confidence limits will be calculated for the proportion of patients with objective response in each 
arm. 
Additional supplementary Bayesian subgroup analyses may be performed by the sponsor. To 
guard against random high and random low results associated with the analysis of multiple 
subgroups for which the trial was not powered and some of which may be small, these Bayesian 
subgroups analyses will be performed using R based on methodology as per Dixon and Simon 
(1991). 
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8.5.1. EORTC-QLQ-C30 QoL 
The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 
3.0) is a validated instrument to measure quality of life and assess symptoms and side effects of 
treatment and their impact on everyday life. Analysis of the EORTC-QLQ-C30 QoL data will be 
performed in the PRO (3rd line+) set. 
The instrument is composed of 5 multi-item functional scales (physical, role, social, emotional 
and cognitive functioning), a global health status/QoL scale, 3 symptom scales (fatigue, 
nausea/vomiting and pain), and 6 single items (financial difficulties, appetite loss, diarrhea, 
constipation, insomnia and dyspnea). Most items are scaled 1 to 4 except the items contributing 
to the global health status/QoL, which are 7-point questions. Raw scores will be transformed using 
a linear transformation to standardize the results so that scores range from 0 to 100. 
The calculation for scoring these scales is the same in all cases: 
1. Calculate the average of the items that contribute to the scale; this is the raw score. 
2. Use a linear transformation to standardize the raw score, so that scores range from 0 to 
100; a higher score represents a higher (i.e. better) level of functioning, or a higher (i.e. 
worse) level of symptoms. 
Calculations for raw score and linear transformation are as follows: 
Let items 
 be included in a scale, where   is number of items in the scale, then: 
 
 
To obtain the score for functional scales: 
 
To obtain the score for symptom scales/items and global health status/QoL: 
 
Range is the difference between the maximum possible value of RS and the minimum possible 
value. 
The structure of the EORTC-QLQ-C30 questionnaire is presented in Scoring for QLQ-C30 
version 3.0 
Table 4 in Appendix 14.3). 
At each assessment point, summary statistics of absolute scores and changes from baseline will 
be calculated by treatment arm for each scale for both the raw score and the linear transformed 
score. The baseline result will be the mean of the screening visit score and the score at last 
assessment prior to dosing. Summary tables and boxplots of the score by visit and treatment arm 
will be presented. The best and worst changes from baseline and associated time points will also 
be summarized using descriptive statistics. For functional scales and global health status, best 
changes from baseline are positive changes; while for symptom scales/items, best changes are 
negative changes. 
The percentage of patients missing the entire questionnaire will be summarized and reason it is 
missing will be listed by treatment arm. 
If more than 50% of questions are unanswered within a subscale at a particular timepoint, the 
value for the subscale will be set to missing. If less than 50% of questions are unanswered, the 
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sum of the scores for the answered questions will be taken and scaled up in relation to the number 
of questions in the scale answered or not. 
The change from baseline for the linear transformed score will be compared between treatment 
arms for the PRO (3rd line+) set using mixed model repeated measures (MMRM) analysis with 
fixed effect terms for treatment arm, visit, treatment arm by visit interaction, the randomization 
stratification factors and also with baseline score as a covariate. Patient will be included as a 
random effect. The default estimation method of Restricted Maximum Likelihood (REML) and 
the Kenward-Roger (KR) option for degrees of freedom will be used. An unstructured covariance 
matrix will be used to model the within-patient error. If the fit of the unstructured covariance 
structure fails to converge, the following covariance structures will be tried in order until 
convergence is reached: Toeplitz with heterogeneity, autoregressive with heterogeneity, toeplitz, 
and autoregressive. A summary table will present number of subjects in each treatment group at 
each visit, LSMeans by treatment arm by visit, along with the difference in LSMeans, standard 
error, 95% CI and 2-sided p-value. 
Patients will also be classified as improved, stable, or worsened. Minimal important difference 
(MID) thresholds, a threshold of 5 score points of the linear transformed score, will be used to 
categorize patients as improved, stable, or worsened. The first post-baseline assessment where 
either improved or worsened status is met will be used to assign patient status. The improved or 
worsened status has to be confirmed by the assessment at subsequent cycle. 
The proportion of patients with each status will be calculated for each subscale based on patients 
who have at least two available change from baseline of the linear transformation scores in that 
scale. A proportional odds model will be used to test the difference in proportions of patient status 
between treatment arms for each scale; a fixed effect term for treatment will be included and the 
model will be stratified for randomization stratification factors. The odds ratio, 95% CI and 2- 
sided p-value will be extracted from the model and presented. 
The individual questions and derived scales scores will be listed for the PRO (3rd line+) set. 
8.5.2. EQ-5D 
EQ-5D is a standardized measure of health status developed by the EuroQol Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal. Analysis of the 
EQ-5D data will be performed for the PRO (3rd line+) set. 
The EQ-5D consists of two parts, the EQ-5D descriptive system and the EQ Visual Analogue 
Scale (EQ VAS). 
EQ-5D Descriptive System 
The EQ-5D descriptive system comprises 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression). Each dimension has 5 levels (no problems, slight problems, 
moderate problems, severe problems, and extreme problems). The respondent is asked to indicate 
his/her health state or placing a cross in the box against the most appropriate level within each of 
the 5 dimensions. This decision results in a 1-digit number expressing the level selected for that 
dimension. The user guide emphasizes that the numerals 1-5 for each level have no arithmetic 
properties and should not be used as a cardinal score. Ambiguous item values (e.g. 2 levels are 
ticked for a single dimension) will be treated as missing values. 
For the 5 dimensions within the descriptive, at each assessment point, the number and percentage 
of patients responding in each of the 5 levels will be presented in a table as well as displayed by 
treatment arm. The number of missing responses will also be displayed. The response profile for 
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each of the 5 dimensions will be compared between treatment arms over time using generalized 
estimating equations (GEE). The marginal model will take the form 
 
where 
denotes expectation, 
is one of the 5 dimensions, 
is the level of the 
dimension, 
,       is the intercept term 
associated with level 
, 
is the treatment arm indicator, 
is the 
visit indicator,      are the regression parameters associated with treatment arm level 
 , 
 
are the regression parameters associated with visit 
and 
are the 
regression 
parameters associated with treatment arm and visit . 
Results will be displayed as well as presented in a table, in terms of the overall odds ratio for 
balixafortide + eribulin vs eribulin monotherapy along with the associated 95% CI and 2-sided p- 
value. Odds ratios by visit will be displayed also. 
EQ VAS 
-rated health visual analogue scale with endpoints labelled 
 
 
There will be no programming checks for a 
discrepancy between where the patient has placed the X and the number they have written in the 
box, the number in the box is the only value available on the database and to be used for analysis. 
EQ VAS scores will be analyzed across visits using an MMRM approach in the same manner as 
described in Section 8.5.1 for the EORTC-QLQ-C30. 
 
8.5.3. FACT-B 
The FACT-B (version 4) is a self-administered questionnaire designed for patients suffering from 
breast cancer; FACT-B is a breast cancer subscale added to the Functional Assessment for Cancer 
Therapy General (FACT-G). It consists of 37 questions grouped into 5 subscales being: 
Physical well-being (7 questions GP1 to GP7, min score=0, max score=28) 
Social/family well-being (7 questions GS1 to GS7, min score=0, max score=28) 
Emotional well-being (6 questions GE1 to GE6, min score=0, max score=24) 
Functional well-being (7 questions GF1 to GF7, min score=0, max score=28) 
Breast subscale (10 questions B1 to B9 and P2, min score=0, max score=40) 
All questions are presented with answers on a five-point (0 to 4) Likert scale. As displayed in 
Appendix 14.4, subscale scores are calculated by first transforming all question scores within a 
subscale to have the same direction such that the higher the score, the better the QOL, and then 
summing the resulting scores. If more than 50% of questions are unanswered within a subscale at 
a particular timepoint, the value for the subscale will be set to missing. If less than 50% of 
questions are unanswered, the sum of the scores for the answered questions will be taken and 
scaled up in relation to the number of questions answered or not in the scale. The subscale scores 
will be combined as follows: 
 
FACT-G total score: PWB score + SWB score + EWB score + FWB score 
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FACT-B total score: PWB score + SWB score + EWB score + FWB score + BCS score 
 
 
No imputation will be done if any of the subscores is missing. 
Analysis of the FACT-B data will be performed in the PRO set. The 5 subscale scores along with 
the FACT-G score and FACT-B total score will be summarized by treatment arm at each 
assessment point using mean, median, standard deviation, min, max and N. 
Each of the subscale scores together with the FACT-G score, FACT-B total score will be analyzed 
over time using an MMRM approach in the same manner as described for the EORTC-QLQ-C30. 
 
8.5.4. Relationship between biomarkers and clinical outcomes 
Relation between biomarkers and clinical outcome will be treated in a separate analysis plan. 
 
8.5.5. Response in patient who continue study treatment despite progression 
Response in patients who continue study treatment despite progression will be assessed according 
to iRECIST (2017) by Investigator. A summary table of counts and percentage of patients 
experiencing each of CR or PR measured at an assessment date later than PD, by visit will be 
presented by treatment arm. Analyses on patients who continue study treatment after the 
progression will be descriptive only because these patients did not go through a second 
randomization process and can be affected by selection bias. 
 
8.5.6. Baseline Tumor Samples 
Archival Tumor Tissue and Fresh Tumor Biopsy information will be listed for the ITT (3rd line+) 
set. 
 
9. Safety Analysis 
Safety data will be assessed in the 3rd line+ and overall (2nd line+) populations. Safety data 
collected in this study includes AEs, serious adverse events (SAEs), clinical laboratory tests, vital 
signs, physical examination, electrocardiogram, and other safety data including pregnancy during 
exposure and medication errors. To maximize the ability to discern safety signals, safety and AE 
data will be summarized on the Safety and Safety (3rd line+) sets, i.e. the overall and 3rd line+ 
population and will be presented for balixafortide + eribulin and eribulin monotherapy treated 
patients. All safety data will be presented in data listings. 
 
9.1. Adverse Events 
Adverse events will be coded by SOC and preferred term using the latest MedDRA dictionary. 
Adverse event severity will be based on NCI CTCAE Grade (version 5.0). 
All AEs reported from the first dose of study treatment (Cycle 1 Day 1 for balixafortide + eribulin 
or Cycle 1 Day 2 for eribulin monotherapy) until 30 days after the last dose of study treatment 
will be considered as treatment-emergent AEs (TEAEs). A TEAE is an AE that was not present 
prior to first dose of study treatment but appeared following treatment or was present prior to the 
start of study treatment but worsened thereafter. An AE that was present prior to the start of study 
treatment, resolved and then reappeared following first dose of study treatment, is a TEAE. If the 
start date of an AE is incomplete and cannot be categorized as occurring before or after the first 
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dose of study treatment, then the AE will be considered as a TEAE. If the start time of the AE is 
presented, then the AE start date and time will be used to classify the AE as TEAE or not. If the 
start time is not provided and the AE occurs on the same day of first dose of study treatment, then 
the AE will be classified as a TEAE. 
 
9.1.1. Incidence of Adverse Events 
AE data will be descriptively summarized by treatment arm. The incidence of TEAEs by 
MedDRA SOC, preferred term, and Investigator attributed relationship (related/not related) to 
balixafortide and/or eribulin, as relevant, will be summarized. AEs will be summarized in terms 
of frequency and percentage. For patient level of summaries, patients with multiple occurrences 
of events of the same preferred terms and SOC will be counted once for each preferred term or 
SOC (at the highest severity/grade and the closest relationship to study treatment as applicable). 
The summary tables will be ordered by descending incidence of SOC and by descending incidence 
of preferred term within each SOC class for all patients. 
The following adverse events summaries will be provided: 
TEAEs by System Organ Class and Preferred Term 
TEAEs by System Organ Class and Preferred Term and CTCAE Grade 
Grade 3 or Higher TEAEs by System Organ Class and Preferred Term 
Grade 3 TEAEs by System Organ Class and Preferred Term 
Grade 4 TEAEs by System Organ Class and Preferred Term 
Serious TEAEs by System Organ Class and Preferred Term 
Serious TEAEs by System Organ Class and Preferred Term and CTCAE Grade 
TEAEs Related to Study Treatment by System Organ Class and Preferred Term 
TEAEs Related to Study Treatment by System Organ Class and Preferred Term and 
CTCAE Grade 
TEAEs Leading to Study Treatment Discontinuation by System Organ Class and Preferred 
Term 
TEAEs Leading to Study Treatment Discontinuation by System Organ Class and Preferred 
Term and CTCAE Grade 
TEAEs with fatal outcome by System Organ Class and Preferred Term, being AEs with 
study treatment 
 
System Organ Class and Preferred Term 
TEAEs of Special Interest by Special Interest Group 
TEAEs of Particular Interest by Particular Interest Group 
All adverse events will be presented in a listing. Furthermore, listings will be presented 
specifically for SAEs, TEAEs leading to study treatment discontinuation and TEAEs leading to 
death. 
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In addition, the number of TEAEs leading to first eribulin dose reduction will be summarized by 
cycle and day of onset, in total and split by treatment arm. 
 
9.1.2. Severity of Adverse Event 
The severity that will be presented represents the most extreme severity captured on the eCRF 
page. The possible severities are measured on the CTCAE scale which goes from 1 to 5 where 
- 
Treatment-emergent AEs 
with a missing severity will be summarized in tables as Grade 3 but will be presented in the data 
listing with a missing severity. 
In the TEAE severity table, if a patient reported multiple occurrences of the same TEAE, only the 
most severe will be presented. A further summary table of only those TEAEs with CTCAE grade 
3 or higher will also be presented. 
 
9.1.3. Serious Adverse Events 
A SAE is defined in the protocol as any event that: results in death, is immediately life threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent 
or significant disability/incapacity, or is a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered SAEs when, based upon medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed above. A summary 
table will be presented, together with a further summary table by CTCAE grade. 
 
9.1.4. Relationship of Adverse Events to Study Treatment 
The investigator will provide an assessment of the relationship of the event to each of balixafortide 
Treatment- 
 
but will be presented in the data listing with a missing relationship. 
A summary table of related TEAEs will be presented, together with a further summary table by 
CTCAE grade. 
 
9.1.5. Adverse Events Leading to Study Treatment Discontinuation 
Following the AE, the investigator will record the action taken with each of the study treatments. 
considered as leading to study treatment discontinuation. The summary table will present overall 
covering all treatment discontinuations, and separately for each of balixafortide and eribulin 
A summary table by CTCAE 
grade will also be presented. 
 
9.1.6. Deaths 
An AE 
All deaths and 
primary reason for patient death will be summarized by treatment arm; deaths within 30 days of 
the last dose of randomized treatment trial drug will be included. Additionally, deaths related to 
study treatment will be summarized by treatment arm. 
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9.1.7. Subgroup Evaluation of Adverse Events 
AEs will be also summarized for the following subgroups: 
 
Bone metastases at baseline (Yes vs No) 
Liver metastases at baseline (Yes vs No) 
9.1.8. Adverse Events of Special and Adverse Events of Particular Interest 
Adverse Events of Special Interest (AESI) and Adverse Events of Particular Interest (AEPI) will 
be identified by the investigator and specified in the eCRF. 
The list of AESI is: Hypersensitivity or IRRs (serious), Neutropenia (serious), Neutropenic 
infections, Febrile neutropenia, Renal impairment. 
The list of AEPI is: Thrombocytopenia, Peripheral neuropathy, Hepatic impairment, QTc 
prolongation, Hypersensitivity/IRRs, Neutropenia (serious), Neutropenic infections, Febrile 
neutropenia and Renal impairment. 
The number and percent of patients reporting an AESI or an AEPI will be summarized by 
treatment arm, MedDRA SOC and Preferred term. All AESI categories will be summarized, while 
only the following categories will be summarized for AEPI: Hypersensitivity/IRRs, 
Thrombocytopenia, QTc prolongation, Peripheral neuropathy and Hepatic impairment. 
Number of patients reporting at least one event of Hypersensitivity/IRR, Neutropenia (serious) or 
Febrile neutropenia will also be summarized by maximum severity (Grade 1 to 5) and treatment 
arm. 
The number of patients reporting Neutropenic infections will be summarized by treatment arm 
and maximum severity (Grade 1 to 5). This table will only be populated when at minimum 4 
patients reported at least 1 event of Neutropenic infection and the number of such patients is more 
than 1% of the Safety population. 
The number of Colony Stimulating Factor (CSP) medications will be summarized for all patients 
experiencing Neutropenia events. 
The number of Hypersensitivity/IRRs and Neutropenia (serious) will be summarized by cycle, 
day of onset, in total and split by treatment arm. The number of all Hypersensitivity/IRR will also 
be summarized in terms of the event intensity allowing for multiple reactions within a patient 
total; the latter will be achieved by means of a Negative Binomial analysis with a fixed effect term 
for randomized treatment and time exposed to randomized treatment as the offset. The rate ratio 
and the corresponding 95% confidence interval will be obtained based on the Wald approach using 
the log as link function. 
Neutropenia (serious) and Febrile neutropenia events will be listed reporting the cycle and day of 
onset and the duration of the event. The time spent experiencing Neutropenia (serious) and Febrile 
neutropenia will be summarized by treatment group and severity using the Probability of Being 
in Event Function, as described by Begg and Larsson (1982). 
Separate Kaplan-Meier analysis will be conducted to describe the time to onset of the AESI and 
AEPI for both treatment arms. Time to onset (months) is defined and calculated as (the earliest 
date of event onset date of first dose + 1)/30.4375. Patients who did not develop the event will 
be censored at their date of death, last trial visit, or the start date of new anti-cancer therapy, 
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whichever is earlier. Median time to onset and its 95% CI will be estimated for both treatment 
arms. If the median time to event cannot be estimated due to lack of events, the 25th percentile 
and its 95% CI will be reported. 
 
9.2. Clinical Laboratory Evaluations 
All safety laboratory evaluations will be done at local laboratories. Blood and urine samples for 
laboratory analysis are collected at Screening, on Day 1 and Day 8 of each cycle for balixafortide 
+ eribulin, on Day 2 and Day 9 of each cycle for eribulin monotherapy, and at the end of treatment 
visit. The results of Day 1 for balixafortide + eribulin and Day 1 and Day 2 for eribulin 
monotherapy will be presented together. The results of Day 8 for balixafortide + eribulin and Day 
8 and Day 9 for eribulin monotherapy will be presented together. 
For hematology and biochemistry, absolute values and changes from baseline will be summarized 
by study treatment arm and cycle/day number. Change from baseline will be calculated as (value 
at a treatment cycle/day value at baseline). 
For those parameters where NCI CTCAE v5.0 grades are derivable, shift tables from baseline to 
each post-baseline time point will be presented by NCI CTCAE v5.0 grades. For all the other 
parameters, shift tables will be presented by analysis range (normal, high or low). For any shift 
table, percentages will be calculated using available data per cycle/day number for each laboratory 
parameter. 
All safety laboratory test results will be summarized by study treatment arm, overall, by cycle and 
by day and also presented in data listings. Coagulation parameters (International Normalized 
Ratio [INR] and prothrombin time) will be listed only. Boxplots of mean ± standard error at each 
cycle/day number will be created for each parameter. 
Urinalysis data will be listed only. 
 
9.2.1. Hematology 
The following parameters will be assessed: white blood cell (WBC) count with differential, red 
blood cell (RBC) count, hemoglobin (Hb), hematocrit (Ht), platelet count, Neutrophils, 
Lymphocytes, Eosinophils, Monocytes and Basophils. 
 
9.2.2. Biochemistry 
The following parameters will be assessed: albumin, total protein, alanine aminotransferase 
(ALT), aspartate transaminase (AST), total bilirubin (TBL), direct bilirubin, indirect bilirubin, 
gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), glucose, creatinine, blood urea 
nitrogen (BUN), urea, creatine kinase (CK), calcium (Ca), potassium (K), sodium (Na), and 
magnesium (Mg). 
Potential cases of drug induced liver injury will be listed and summarized by treatment arm. 
Potential cases of drug induced liver injury are defined using concurrent ALT, AST and TBL as 
follows: 
For patients with all 3 parameters (ALT, AST and TBL) within the normal range at 
baseline: 
o ALT or AST 
TBL 
with 
no evidence of hemolysis and an ALP value 
; 
For patients with pre-existing ALT or AST values above the ULN at baseline: 
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o (ALT or AST)   2 x baseline and (ALT or AST) 
and TBL   2 x ULN. 
Note that the double criterion on (ALT or AST) requires values 
of 2 x baseline and 3 x ULN which ensures an increase from baseline even in the 
case of a very large baseline value >3 x ULN; 
o As above with additional more stringent criterion of (ALT or AST) 
. 
For patients with pre-existing values of total bilirubin above the normal range at baseline: 
o (ALT or AS 
and (TBL>= baseline + ULN and 
); 
o As above with additional more stringent criterion of (ALT or AST) 
. 
A log-log plot of maximum ALT/AST/ALP vs maximum total bilirubin will be created to identify 
potential cases of concern. Additionally, an individual profile over time for each ULN-normalized 
liver function test (ALT, ALP, AST and TBL) will be plotted for all the potential cases. 
 
9.2.3. Urinalysis 
The following parameters will be assessed: appearance, color, dipstick (pH, Specific gravity, 
ketones, protein, glucose, blood, bilirubin, nitrite, leukocytes, bacteria, casts, crystals, epithelial 
cells, red blood cells, white blood cells and other results). Microscopic analysis if warranted by 
Dipstick results. Bacteria, casts, crystals, epithelial cells, red blood cells, white blood cells and 
other results come under the microscopic analysis on the eCRF. 
 
9.3. Vital Sign Measurements 
Weight, BSA, body temperature and resting blood pressure and respiratory and pulse rate will be 
measured in all patients at Screening, and at the EoT visit. 
Weight and vital signs will also be assessed on Day 1 of each cycle for patients on the balixafortide 
+ eribulin treatment arm and on Day 2 of each cycle for patients on the eribulin monotherapy 
treatment arm. 
The vital sign results and changes from baseline will be summarized by cycle and treatment arm. 
A data listing will be produced as well. 
 
9.4. Physical Examination 
Physical examination will be performed at Screening, on Day 1 of each cycle for patients on the 
balixafortide + eribulin treatment arm and on Day 2 of each cycle for patients on the eribulin 
monotherapy treatment arm and in all patients at the EoT visit. 
A summary table for the shift from baseline to post-baseline timepoints for physical exam will be 
presented by treatment arm. All physical examination results will be presented in a data listing. 
 
9.5. Electrocardiogram 
An electrocardiogram (ECG) will be performed at the clinical site during the visits and timepoints 
shown below. 
 
Treatment 
Arm 
Visit 
Day 
ECG Timepoint 
ECG 
Type 
All 
Screening 
-21 to -1 
Anytime 
12-lead 
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Treatment 
Arm 
Visit 
Day 
ECG Timepoint 
ECG 
Type 
Balixafortide + 
eribulin 
Cycle 1 
1 
Within 1 hour prior to administration 
of balixafortide 
Duplicate 
12-lead 
Balixafortide + 
eribulin 
Cycle 1 
2 
Immediately 
before 
starting 
the 
balixafortide infusion 
12-lead 
Eribulin 
monotherapy 
Cycle 1 
2 
Immediately 
before 
starting 
the 
eribulin infusion 
12-lead 
All 
Cycle 1 
2 
Within 1 hour after completing the 
eribulin infusion 
12-lead 
Balixafortide + 
eribulin 
Cycle 1 
9 
Immediately 
before 
starting 
the 
balixafortide infusion 
12-lead 
Eribulin 
monotherapy 
Cycle 1 
9 
Immediately 
before 
starting 
the 
eribulin infusion 
12-lead 
All 
Cycle 1 
9 
Within 1 hour after completing the 
eribulin infusion 
12-lead 
Balixafortide + 
eribulin 
Cycle 2 & 
subsequent 
cyclesa 
2 
Immediately 
before 
starting 
the 
balixafortide infusion 
12-lead 
Eribulin 
monotherapy 
Cycle 2 & 
subsequent 
cyclesa 
2 
Immediately 
before 
starting 
the 
eribulin infusion 
12-lead 
All 
Cycle 2 & 
subsequent 
cyclesa 
2 
Within 1 hour after completing the 
eribulin infusion 
12-lead 
Balixafortide + 
eribulin 
Cycle 2 & 
subsequent 
cyclesa 
9 
Immediately 
before 
starting 
the 
balixafortide infusion 
12-lead 
Eribulin 
monotherapy 
Cycle 2 & 
subsequent 
cyclesa 
9 
Immediately 
before 
starting 
the 
eribulin infusion 
12-lead 
All 
Cycle 2 & 
subsequent 
cyclesa 
9 
Within 1 hour after completing the 
eribulin infusion 
12-lead 
All 
EoT 
- 
Anytime 
12-lead 
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a: After Cycle 2, the frequency of ECG recordings can be reduced to every 2 cycles if deemed 
clinically appropriate (i.e. absence of ECG findings in earlier assessments). 
 
ECG measurements include Ventricular rate, PR interval, QT interval, QTcF interval, RR interval, 
and QRS duration. Summary tables of ECG results will be presented and changes from baseline 
will be summarized by treatment arm and by cycle, by day and by ECG timepoint. Any clinically 
significant changes will be recorded as AEs. 
QTcF intervals between >480 
 
3) will be identified and summarized by study treatment arm, by cycle, by day and by ECG 
timepoint. 
 
9.6. Other Safety Data 
 
9.6.1. Medication Errors 
The number of dosing errors will be summarized for each medication error event (Overdose, 
Consumption of the study treatment by the wrong patient, Other) by visit and overall. All the other 
variables collected for study medication errors will be listed only. 
 
9.6.2. ECOG Performance Score 
ECOG performance score at each timepoint and its change from baseline will be summarized by 
treatment arm. The data will also be listed. 
 
9.6.3. Exposure during pregnancy 
Pregnancy outcomes during exposure will be handled outside this execution plan, and relevant 
details will be documented in the Clinical Study Report. 
 
10. Pharmacokinetics 
Pharmacokinetics and Immunogenicity will be treated in a separate analysis plan. 
 
11. Interim Analysis 
A DSMB is established with the responsibility of safeguarding the safety of study participants. 
The DSMB will review accumulating safety data during the conduct of the study and the interim 
analyses. The DSMB will provide ongoing review and recommendations to the Sponsor as 
necessary in relation to study conduct and patient management. 
The DSMB charter will describe the operational aspects of the DSMB and the analytical and 
monitoring plan for the study. The Charter will further state the primary responsibilities of the 
DSMB, its relationship with Polyphor, its membership, and the purpose and timing of its meetings, 
statistical monitoring guidelines to be implemented, and statistical analysis for open and closed 
sessions. The DSMB Charter and meeting minutes will be submitted as part of the final Clinical 
Study Report. 
 
12. Changes in the Planned Analysis 
The changes from planned analyses described in the protocol and in the Statistical Analysis Plan 
(SAP) version 1.4 dated 18Jan2019 to those presented in this execution plan are the followings: 
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Added PP set definition and analysis of coprimary endpoints: PFS and OS in PP (3rd line+ 
confirmed) set. Clarified definition of 3rd line+ Confirmed in analysis sets is based on 
randomization strata and eCRF data. 
Added sensitivity analysis for PFS and OS in ITT 3rd line+ (ITT 3rd line+ Confirmed and 
PP 3rd line+ Confirmed). 
Added sensitivity analysis for ORR in RE 3rd line+ (RE 3rd line+ Confirmed). 
Data listings for prior systemic cancer/oncology therapies will include only dose, unit, 
dose regimen, frequency, best response to cancer therapy, and reason for discontinuation 
(toxicity, other or progressive disease). 
For this study, up to three (3) intervening NEs will be allowed to confirm a CR or PR. 
Subsequent documentation of a CR may provide confirmation of a previously identified 
CR with up to three (3) intervening non- evaluable (NE) assessments (e.g. CR NE CR, CR 
NE NE CR, or CR NE NE NE CR). Similarly, subsequent documentation of a PR may 
provide confirmation of a previously identified PR with up to three (3) intervening NEs 
(e.g., PR NE PR, PR NE NE PR, or PR NE NE NE PR). However, only one (1) intervening 
SD will be allowed between PRs for confirmation (i.e., PR SD PR). 
Listing of patients with clinically significant abnormalities in vital signs has been 
removed. 
All AESIs and only the non-overlapping categories for AEPIs will be summarized by 
treatment arm, MedDRA SOC, Preferred term, and toxicity grade. 
Prior anticancer therapies will not be summarized as regimens since regimens are not 
identified in eCRF. Individual therapies instead of regimens will be reported. 
Subgroups have been updated in the exploratory efficacy endpoints, section 8.5. 
COVID section added 
Medication errors will not be reported by MedDRA. Instead, they will be reported by 
medication error event overall and at each visit. 
 
13. References 
Begg BB, Larson M. A study of the use of the Probability-of-being-in-response function 
as a summary of tumor response data. Biometrics 1982; 38:59 66. 
Ellis S, Carroll KJ and Pemberton K. Analysis of Duration of Response in Oncology 
Trials. Contemporary Clinical Trials, 2008; 29: 456 465. 
Carroll, KJ. Back to basics: explaining sample size in outcome trials, are statisticians 
doing a thorough job? Pharm Stats, 2009; 8: 333 345. 
Dixon D and Simon R. Bayesian Subset Analysis. Biometrics, 1991; 47:871-881. 
MedDRA Dictionary (https://www.meddra.org/) 
NCI CTCAE Grade 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
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Sampson HA. Second Symposium on the Definition and Management of Anaphylaxis: 
Summary Report Second National Institute of Allergy and Infectious Disease/Food 
Allergy and Anaphylaxis Network Symposium. Annals of Emergency Medicine. 
2006;47(4):373-80. 
FDA 2009. Guidance for industry. Drug-induced livery injury: premarketing clinical 
evaluation. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM174090.pdf 
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14. Appendices 
 
14.1. 
General Schedule of Assessments 
 
14.1.1. Schedule of Assessments for Balixafortide + Eribulin Treatment Arm 
 
Table 2 - Schedule of Assessments for Balixafortide + Eribulin Treatment Arm: Screening, Cycle 1, and Cycle 2 
 
Visits (Visit 
Window days) 
Screening 
(-21 to -1) 
Active treatment phase (21 Days per cycle) 
Cycle 1 
Cycle 2 
D1 
D2 
D3 
D8 
D9 
D10 
D1 
D2 
D3 
D8 
D9 
D10 
D21 
Assessment 
Informed consent 
X 
IWRS/IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
Demographics (gender, date of birth, race, 
ethnicity) and baseline data 
X 
Medical history 
X 
Patient reported health outcomes 
X 
X 
X 
Physical examination[1] 
X[2] 
X[3] 
X[3] 
Vital signs (body temperature, resting blood 
pressure, respiratory rate, pulse rate)[1] 
X 
X 
X 
Weight, height[4] 
X 
X 
X 
ECOG performance status 
X 
X 
X 
Adverse events 
X[5] 
X 
X 
Prior/Concomitant medications 
X 
X 
X 
Clinical Laboratory tests[1] 
X[6] 
X[7] 
X[7] 
X[7] 
X[7] 
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Visits (Visit 
Window days) 
Screening 
(-21 to -1) 
Active treatment phase (21 Days per cycle) 
Cycle 1 
Cycle 2 
D1 
D2 
D3 
D8 
D9 
D10 
D1 
D2 
D3 
D8 
D9 
D10 
D21 
Assessment 
Pregnancy test 
X[8] 
X[9] 
X[9] 
Contraceptive advice 
X 
CT/MRI scan[10, 11] 
X[12] 
X[10] 
Bone scan 
X[12, 13] 
12-lead ECG[1] 
X 
X 
X 
X 
X[14] 
X[14] 
Document date and results of last tumor 
biopsy/fresh tumor biopsy 
X 
Blood for PK 
X 
X 
X 
X 
X 
X 
Blood for immunogenicity testing 
X 
X 
X 
X 
Blood for exploratory biomarkers in all 
patients[15] 
X 
X 
X 
X 
X 
Confirmation of eligibility and randomization 
X 
Balixafortide treatment[16] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eribulin treatment 
X 
X 
X 
X 
For patients at selected sites 
Optional tumor biopsy[17] 
X 
X[18] 
Blood for other exploratory biomarkers 
X 
X 
X 
X[19] 
MRI: magnetic resonance imaging; RECIST: Response Evaluation Criteria In Solid Tumors; SAE: serious adverse event. Footnotes: 
1. Additional assessments to those scheduled for this study should be performed as indicated at the Investigator's discretion (e.g. due to 
concerns about patient safety, patient's clinical status); the findings of an unscheduled examination should be recorded in the patient's 
source data and eCRF. 
2. Standard, complete physical examination. 
3. Targeted physical examination. 
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4. Height will be measured at Screening only. 
5. SAEs will be recorded from the date that the informed consent form is signed. 
6. Screening blood tests should be taken within 7 days prior to randomization. 
7. Blood test results must be available within 24 hours prior to study medication administration. 
8. Serum pregnancy test for women of childbearing potential only, no more than 7 days prior to Randomization. More frequent 
assessments can be performed if medically indicated as determined by the Investigator, and these evaluations will be recorded in the 
9. Urine pregnancy test for women of childbearing potential only. 
10. CT/MRI scan will be performed at Screening, then from the date of randomization every 6 weeks (±7 days) during the first year, and 
then every 12 weeks (±7 days), thereafter, until PD is documented by RECIST v1.1. It is critical that tumor assessments are performed 
according to the Study Schedule in a timely and complete manner regardless of any dosing delay or interruption. Imaging assessments 
will be scheduled using the randomization date as the reference date for all timepoints and NOT scheduled according to the date of the 
previous timepoint. A delay in the imaging assessment to accommodate a treatment delay is not permitted. Following initial 
documentation of an objective response, a confirmatory CT/MRI scan will be performed at least 4 weeks later. 
11. At the discretion of the Investigator, additional radiographic tumor assessments may be done at any time if there is clinical suspicion 
of disease progression; the results of the unscheduled scan should be recorded in the patient's source data and eCRF. 
12. Record date and results of last scan on the patient's source data and eCRF. If no scan has been performed in the 30 days prior to 
Randomization a scan should be performed during Screening. 
13. From the date of randomization, additional bone scans will be performed at the discretion of the Investigator. 
14. After Cycle 2, the frequency of ECGs can be reduced to every 2 cycles if deemed clinically appropriate (i.e. absence of ECG findings 
in earlier assessments). 
15. Blood will be collected from all patients to assess plasma levels of interferon gamma and additional cytokine markers. 
16. Patients will start study medication within 3 days from randomization. 
17. Patients at selected sites can optionally consent to fresh tumor biopsy at Screening and subsequent timepoints. If a biopsy has already 
been performed within 30 days prior to Randomization and tumor tissue is still available, then the fresh tumor biopsy is not required 
during Screening. 
18. Alternatively, can be performed on Day 10 if preferred. 
19. A blood sample will be taken only in patients at selected sites who are scheduled to have an optional, fresh tumor biopsy; the blood 
sample can be taken before or after the biopsy. 
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Table 3 - Schedule of Assessments for Balixafortide + Eribulin Treatment Arm: Cycle 3, Subsequent Cycles, and Post-treatment Phase 
 
Visits (Visit 
Window days) 
Active treatment phase (21 Days per cycle) 
Post-treatment phase 
Cycle 3 
Subsequent Cycles 
EoT 
(+7) 
30-day 
safety 
FU (+7) 
Long- 
term FU 
(±7)[1] 
D1 
D2 
D3 
D4 
D5 
D8 
D9 
D10 
D1 
D2 
D3 
D8 
D9 
D10 
D21 
Assessment 
IWRS/IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient reported health 
outcomes 
X 
X 
X 
Targeted physical 
examination[2] 
X 
X 
X 
Vital signs (body 
temperature, resting blood 
pressure, respiratory rate, 
pulse rate)[2] 
X 
X 
X 
Weight 
X 
X 
X 
ECOG performance status 
X 
X 
X 
Adverse events 
X 
X 
Prior/Concomitant 
medications 
X 
X 
X[3] 
Clinical Laboratory tests[2] 
X[4] 
X[4] 
X[4] 
X[4] 
X 
Pregnancy test 
X[5] 
X[5] 
X[5] 
CT/MRI scan[6, 7] 
X[6] 
X[8] 
X[1] 
Bone scan[9] 
12-lead ECG[2] 
X[10] 
X[10] 
X[10] 
X[10] 
X 
Blood for PK 
X 
X[11] 
X[11] 
X[12] 
X[12] 
Blood for immunogenicity 
testing 
X 
X[13] 
X 
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Visits (Visit 
Window days) 
Active treatment phase (21 Days per cycle) 
Post-treatment phase 
Cycle 3 
Subsequent Cycles 
EoT 
(+7) 
30-day 
safety 
FU (+7) 
Long- 
term FU 
(±7)[1] 
D1 
D2 
D3 
D4 
D5 
D8 
D9 
D10 
D1 
D2 
D3 
D8 
D9 
D10 
D21 
Assessment 
Blood for exploratory 
biomarkers in all patients[14] 
X 
X 
X 
X[15] 
X[15] 
X 
X 
Balixafortide treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eribulin treatment 
X 
X 
X 
X 
Document reason for 
treatment discontinuation 
X 
Survival status, PD 
monitoring, all anticancer 
medicines received 
X 
For patients at selected 
sites 
Optional tumor biopsy 
X 
Blood for other exploratory 
biomarkers 
X 
X 
X 
 
AE: adverse event; MRI: magnetic resonance imaging; RECIST: Response Evaluation Criteria In Solid Tumors. Footnotes: 
1. Regardless of treatment arm, patients discontinued from study medication for any reason, in the absence of PD, will undergo repeat 
imaging and tumor response assessments (including CT/MRI scans) every 8 weeks ±7 days (every 12 weeks ±7 days if the patient has 
  year) until PD is documented as per RECIST v1.1, or death occurs, or the patient is lost to follow-up, or the 
patient withdraws consent (whichever occurs first). Once PD is recorded, the patient will be followed every 6 months (or more 
frequently) for Survival Follow-up only, until the patient dies, withdraws consent, or is lost to follow-up (whichever occurs first). 
Survival follow-up can be conducted by telephone. 
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2. Additional assessments to those scheduled for this study should be performed as indicated at the Investigator's discretion (e.g. due to 
concerns about patient safety, patient's clinical status); the findings of an unscheduled examination should be recorded in the patient's 
source data and eCRF. 
3. Concomitant therapy/medications taken since previous visit to be recorded for patients with unresolved AEs. 
4. Blood test results must be available within 24 hours prior to study medication administration. 
5. Urine pregnancy test for women of childbearing potential only. 
6. CT/MRI scan will be performed at Screening, then from the date of randomization every 6 weeks (±7 days) during the first year, and 
then every 12 weeks (±7 days), thereafter, until PD is documented by RECIST v1.1. It is critical that tumor assessments are performed 
according to the Study Schedule in a timely and complete manner regardless of any dosing delay or interruption. Imaging assessments 
will be scheduled using the randomization date as the reference date for all timepoints and NOT scheduled according to the date of the 
previous timepoint. A delay in the imaging assessment to accommodate a treatment delay is not permitted. Following initial 
documentation of an objective response, a confirmatory CT/MRI scan will be performed at least 4 weeks later. 
7. At the discretion of the Investigator, additional radiographic tumor assessments may be done at any time if there is clinical suspicion 
of disease progression; the results of the unscheduled scan should be recorded in the patient's source data and eCRF. 
8. CT/MRI scans will be performed in patients who are discontinued from study medication in the absence of PD; however, patients who 
have already demonstrated objective PD (according to RECIST v 1.1) do not need to have scans repeated at the EoT visit. 
9. From the date of randomization, additional bone scans will be performed at the discretion of the Investigator. 
10. After Cycle 2, the frequency of ECGs can be reduced to every 2 cycles if deemed clinically appropriate (i.e. absence of ECG findings 
in earlier assessments). 
11. For patients at selected sites only. 
12. Cycle 5 and Cycle 7 only. 
13. After Cycle 3, blood samples are taken on Day 1 of every alternate cycle (e.g. Cycle 5, Cycle 7, Cycle 9 etc). 
14. Blood will be collected from all patients to assess plasma levels of interferon gamma and additional cytokine markers. 
15. Only in patients at selected sites scheduled to have PK sampling. 
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14.1.2. Schedule of Assessments for Eribulin Monotherapy Treatment Arm 
 
Screening 
(-21 to -1) 
Active treatment phase (21 Days per cycle) 
Post-treatment phase 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent Cycles 
EOT 
(+7) 
30-day 
safety FU 
(+7) 
Long-term 
FU (±7)[1] 
D2 
D9 
D2 
D9 
D21 
D2 
D9 
D2 
D9 
D21 
Assessment 
Informed consent 
X 
IWRS/IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
Demographics (gender, date of birth, 
race, ethnicity) and baseline data 
X 
Medical history 
X 
Patient reported health outcomes 
X 
X 
X 
X 
X 
X 
Physical examination[2] 
X[3] 
X[4] 
X[4] 
X[4] 
X[4] 
X[4] 
Vital signs (body temperature, resting 
blood pressure, respiratory rate, pulse 
rate)[2] 
X 
X 
X 
X 
X 
X 
Weight, height[5] 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
Adverse events 
X[6] 
X 
X 
Prior/Concomitant medications 
X 
X 
X 
X[7] 
Clinical laboratory tests[2] 
X[8] 
X[9] 
X[9] 
X[9] 
X[9] 
X[9] 
X[9] 
X[9] 
X[9] 
X 
Pregnancy test 
X[10] 
X[11] 
X[11] 
X[11] 
X[11] 
X[11] 
Contraceptive advice 
X 
CT/MRI scan[12,13] 
X[14] 
X[12] 
X[12] 
X[15] 
X[1] 
Bone scan 
X[14, 16] 
12-lead ECG[2] 
X 
X 
X 
X [17] 
X[17] 
X[17] 
X[17] 
X[17] 
X[17] 
X 
Document date and results of last tumor 
biopsy/fresh tumor biopsy 
X 
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Screening 
(-21 to -1) 
Active treatment phase (21 Days per cycle) 
Post-treatment phase 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent Cycles 
EOT 
(+7) 
30-day 
safety FU 
(+7) 
Long-term 
FU (±7)[1] 
D2 
D9 
D2 
D9 
D21 
D2 
D9 
D2 
D9 
D21 
Assessment 
Blood for exploratory biomarkers in all 
patients[18] 
X 
X 
X 
X 
Confirmation of eligibility and 
randomization 
X 
Eribulin treatment[19] 
X 
X 
X 
X 
X 
X 
X 
X 
Document reason for treatment 
discontinuation 
X 
Survival status, PD monitoring, all 
anticancer medicines received 
X 
For patients at selected sites 
Optional tumor biopsy[20] 
X 
X 
X 
Blood for other exploratory biomarkers 
X 
X[21] 
X 
X 
AE: adverse event; RI: magnetic resonance imaging; RECIST: Response Evaluation Criteria In Solid Tumors; SAE: serious adverse event. 
Footnotes: 
1. Regardless of treatment arm, patients discontinued from study medication for any reason, in the absence of PD, will undergo repeat 
imaging and tumor response assessments (including CT/MRI scans) every 8 weeks ±7 days (every 12 weeks ±7 days if the patient has 
  year) until PD is documented as per RECIST v1.1, or death occurs, or the patient is lost to follow-up, or the 
patient withdraws consent (whichever occurs first). Once PD is recorded, the patient will be followed every 6 months (or more 
frequently) for Survival Follow-up only, until the patient dies, withdraws consent, or is lost to follow-up (whichever occurs first). 
Survival follow-up can be conducted by telephone. 
2. Additional assessments to those scheduled for this study should be performed as indicated at the Investigator's discretion (e.g. due to 
concerns about patient safety, patient's clinical status); the findings of an unscheduled examination should be recorded in the patient's 
source data and eCRF. 
3. Standard, complete physical examination. 
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4. Targeted physical examination. 
5. Height will be measured at Screening only. 
6. SAEs will be recorded from the date that the informed consent form is signed. 
7. Concomitant therapy/medications taken since previous visit to be recorded for patients with unresolved AEs. 
8. Screening blood tests should be taken within 7 days prior to randomization. 
9. Blood test results must be available within 24 hours prior to study medication administration. 
10. Serum pregnancy test for women of childbearing potential only, no more than 7 days prior to Randomization. More frequent 
assessments can be performed if medically indicated as determined by the Investigator, and these evaluations will be recorded in the 
11. Urine pregnancy test for women of childbearing potential only. 
12. CT/MRI scan will be performed at Screening, then from the date of randomization every 6 weeks (±7 days) during the first year, and 
then every 12 weeks (±7 days), thereafter, until PD is documented by RECIST v1.1. It is critical that tumor assessments are performed 
according to the Study Schedule in a timely and complete manner regardless of any dosing delay or interruption. Imaging assessments 
will be scheduled using the randomization date as the reference date for all timepoints and NOT scheduled according to the date of the 
previous timepoint. A delay in the imaging assessment to accommodate a treatment delay is not permitted. Following initial 
documentation of an objective response, a confirmatory CT/MRI scan will be performed at least 4 weeks later. 
13. At the discretion of the Investigator, additional radiographic tumor assessments may be done at any time if there is clinical suspicion 
of disease progression; the results of the unscheduled scan should be recorded in the patient's source data and eCRF. 
14. Record date and results of last scan on the patient's source data and eCRF. If no scan has been performed in the 30 days prior to 
Randomization a scan should be performed during Screening. 
15. CT/MRI scans will be performed in patients who are discontinued from study medication in the absence of PD; however, patients who 
have already demonstrated objective PD (according to RECIST v 1.1) do not need to have scans repeated at the EoT visit. 
16. From the date of randomization, additional bone scans will be performed at the discretion of the Investigator. 
17. After Cycle 2, the frequency of ECGs can be reduced to every 2 cycles if deemed clinically appropriate (i.e. absence of ECG findings 
in earlier assessments). 
18. Blood will be collected from all patients to assess plasma levels of interferon gamma and additional cytokine markers. 
19. Patients will start study medication within 3 days from randomization. 
20. Patients at selected sites can optionally consent to fresh tumor biopsy at Screening and subsequent timepoints. If a biopsy has already 
been performed within 30 days prior to Randomization and tumor tissue is still available, then the fresh tumor biopsy is not required 
during Screening. 
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21. A blood sample will be taken only in patients at selected sites who are scheduled to have an optional, fresh tumor biopsy; the blood 
sample can be taken before or after the biopsy. 
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3rd line+ PFS 
-ve @ a;=0.040 
3rd line+ PFS 
+ve @ a;=0.040 
Overall Popln 
overall Popln 
 
14.2. 
Type I Error Control for Primary and Key Secondary Efficacy Analyses 
Figure 1 - Type I Error Control for Primary and Key Secondary Efficacy Analyses in the 3rd line+ patient population 
 
ORR 
test at a;=0.001 
 
 
+ve 
-ve 
 
 
 
 
 
3rd line+ PFS test at a;=0.040 
OS at interim test at a;=0.002 
3rd line-t PFS test at CL=0.040 
OS at interim test at CL=0.001 
 
 
 
 
 
Final OS test 
at CL=0.050 
3rd line+ PFS 
-ve @ a..=O.040 
3rd line+ PFS 
+ve@ CL=0.040 
Overall Popln 
PFS not   tested 
Overall Popln 
test at a;=0.040 
Interim 
Final OS test 
05-ve 
@ a.=0.008 
Overall Popln PFS-ve 
and Interim OS-ve 
Final OS test 
ata;=0.008 
Interim 
Final OS test 
OS+ve 
@ a.=0.009 
Overa II PopIn PFS -ve 
and Interim OS+ve 
Final OS test 
at a.-=0.009 
Overa II PopIn PFS +ve 
and Interim 05-ve 
Final OS test 
ata;=0.048 
Overa II PopIn PFS +ve 
and Interim OS+ve 
Final OS test 
at a;=0.049 
Overall Popln PFS+ve 
andInterim OS +ve 
PFS not tested 
test at a;c0.040 
nterim 
Final OS test 
OS-ve 
@ a.-=0.008 
Overall Popln PFS-ve 
Final OS test 
and Interim OS-ve 
 at a;:0.008 
Interim 
Final OS test 
OS+ve 
@ a.-=0.010 
Overall Popln PFS-ve 
Final OS test 
and Interim OS +ve 
at CL=0.0111> 
Overall Popln PFS+ve 
Final OS test 
andInterim OS-ve 
 at CL=0.048 
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14.3. 
Scoring for QLQ-C30 version 3.0 
Table 4 - Scoring for QLQ-C30 version 3.0 
 
 
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14.4. 
Subscale Scoring for the FACT-B 
Table 5 - Subscale Scoring for the FACT-B 
 
Subscale 
Item 
Reverse? 
Item response 
Item 
Score 
PHYSICAL 
WELL 
BEING 
(PWB) 
GP1 
Yes 
GP2 
Yes 
GP3 
Yes 
GP4 
Yes 
GP5 
Yes 
GP6 
Yes 
  
GP7 
Yes 
 
Total 
  
 
7 
  
 
Divide by number 
items answered 
 
 
 
 
 
 
 
 
 
 
 
 
 
= PWB subscale score 
SOCIAL/FAMILY 
WELL 
BEING 
(SWB) 
GS1 
No 
GS2 
No 
GS3 
No 
GS4 
No 
GS5 
No 
GS6 
No 
  
GS7 
No 
 
Total 
  
 
7 
  
 
Divide by number 
items answered 
 
 
 
 
 
 
 
 
 
 
 
 
 
= SWB subscale score 
EMOTIONAL 
WELL 
BEING 
(EWB) 
GE1 
Yes 
GE2 
No 
GE3 
Yes 
GE4 
Yes 
GE5 
Yes 
  
GE6 
Yes 
 
 
Total 
  
 
6 
  
 
Divide by number 
items answered 
 
 
 
= EWB subscale score 
 
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Subscale Scoring for the FACT-B (cont.) 
 
 
 
Subscale 
Item 
Reverse? 
Item response 
Item 
Score 
BREAST 
CANCER 
SUBSCALE 
(BCS) 
B1 
Yes 
B2 
Yes 
B3 
Yes 
B4 
No 
B5 
Yes 
B6 
Yes 
B7 
Yes 
B8 
Yes 
x 
B9 
No 
x 
  
P2 
Yes 
x 
 
Total 
  
 
10 
  
 
Divide by number 
items answered 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
=BC subscale score 
FUNCTIONAL 
WELL-BEING 
(FWB) 
GF1 
No 
GF2 
No 
GF3 
No 
GF4 
No 
GF5 
No 
GF6 
No 
  
GF7 
No 
 
Total 
  
 
7 
  
 
Divide by number 
items answered 
 
 
 
 
 
 
 
 
 
 
 
 
 
= FWB subscale score 
 
 
 
 
14.5. 
Algorithm for the best response determination according to RECIST v1.1 
guidelines, as assessed by the local Investigator's review 
 
a) Patients need to have two consecutive assessments of PR or CR to be a responder. PR or 
CR must be confirmed by 2 consecutive tumor evaluations spaced at least 4 weeks (28 
days) apart. 
b) For this study, up to three (3) intervening NEs will be allowed to confirm a CR or PR. 
Subsequent documentation of a CR may provide confirmation of a previously identified 
CR with up to three (3) intervening NEs (e.g., CR NE CR, CR NE NE CR, or CR NE NE 
NE CR). Similarly, subsequent documentation of a PR may provide confirmation of a 
previously identified PR with up to three (3) intervening NEs (e.g., PR NE PR, PR NE NE 
PR, or PR NE NE NE PR). However, only one (1) intervening SD will be allowed between 
PRs for confirmation (i.e., PR SD PR). The following table, based on Appendix from the 
RECIST 1.1 guidelines, summarizes the algorithm describing how Confirmed Response 
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review. The order used to determine the First Time Point response is CR>PR>SD>PD, 
ignoring visits with missing tumor assessments. 
c) The Confirmed Response is determined based on all overall tumor assessments. 
d) Determine the first time point response as the first assessment of the non-confirmed best 
response (CR > PR > SD > PD) for a patient, then take the first occurrence of the non- 
confirmed best response and look at the subsequent assessments within the considered 
period (Results based upon scans performed after start of new anti-cancer therapy will be 
excluded for analysis derivations) using the following rules. 
 
 
Case 
Overall response entered 
in eCRF by investigator 
Confirmed Response (Best Response)* 
First Time 
Point 
Response 
(TPR)** 
Subsequent 
Time Point 
Response 
(TPR) 
1 
CR 
CR 
CR (if assessments at least 4 weeks (28 days) apart). 
(note: sequences of CR NE CR, CR NE NE CR, or CR 
NE NE NE CR would be considered as confirmed CR) 
2 
CR 
PR 
SD, PD or PR 
If CR truly met at first timepoint, any subsequent 
assessment of PR should make the disease PD at that 
point. That is, neither a PR nor SD may follow CR 
Therefore, SD, if CR assessment >=6 weeks (+/-7 
days), i.e. 35 days after date of randomization (i.e. date 
of assessment date of randomiz 
 
otherwise PD. 
However, confirmed response may be PR if subsequent 
scans suggest small lesions were still present at first 
assessment (in which case first assessment of CR 
should be changed to PR) * 
(if assessments at least 4 weeks (28 days) apart). 
3 
CR 
SD 
SD or PD 
SD, if CR or SD assessment >=6 weeks (+/-7 days), i.e. 
35 days after date of randomization, 
otherwise PD 
4 
CR 
PD 
SD or PD 
SD, if CR assessment >=6 weeks (+/-7 days), i.e. 35 
days after date of randomization, 
otherwise PD 
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Case 
Overall response entered 
in eCRF by investigator 
Confirmed Response (Best Response)* 
First Time 
Point 
Response 
(TPR)** 
Subsequent 
Time Point 
Response 
(TPR) 
5 
CR 
NE** 
SD or NE 
SD, if CR assessment >=6 weeks (+/-7 days), i.e. 35 
days after date of randomization 
otherwise NE 
6 
PR 
CR 
PR (if assessments at least 4 weeks (28 days) apart). 
7 
PR 
PR 
PR (if assessments at least 4 weeks (28 days) apart). 
8 
PR 
SD (3) ** 
SD 
9 
PR 
PD 
SD or PD 
SD, if PR assessment >=6 weeks (+/-7 days), i.e. 35 
days after date of randomization, 
otherwise PD 
10 
PR 
NE** 
SD or NE 
SD, if PR assessment >=6 weeks (+/-7 days), i.e. 35 
days after date of randomization, 
otherwise NE 
11 
SD 
SD 
SD 
12 
SD 
PD 
SD or PD 
SD, if SD assessment >=6 weeks (+/-7 days), i.e. 35 
days after date of randomization, 
otherwise PD 
13 
SD 
NE 
SD or NE 
SD, if SD assessment >=6 weeks (+/-7 days), i.e. 35 
days after date of randomization, 
otherwise NE 
14 
CR, PR, SD 
- 
SD or NE 
SD, if assessment >=6 weeks (+/-7 days), i.e. 35 days 
after date of randomization and does not qualify for CR 
or PR, 
otherwise NE. 
15 
PD 
No further 
PD. Ignore all assessments after initial overall response 
of PD. 
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Case 
Overall response entered 
in eCRF by investigator 
Confirmed Response (Best Response)* 
First Time 
Point 
Response 
(TPR)** 
Subsequent 
Time Point 
Response 
(TPR) 
16 
NE 
NE 
NE 
Where all assessments are Not evaluable 
17 
NE 
- 
NE 
* A Best Response of SD can only be made after the subject is on-study for a minimum of six (6) 
weeks (42 days) +/- seven (7) days, for a minimum time on-study of thirty-five (35) days. If the 
subject is on-study less than six (6) weeks (42 days) +/- seven (7) days or thirty-five (35) days, 
any tumor assessment indicating Stable Disease before this time period will have a Best Response 
of NE unless PD is identified. 
** For this study, up to three (3) intervening NEs will be allowed between CRs or PRs but only 
one (1) intervening SD is allowed between PRs. Subsequent documentation of CR may provide 
confirmation of a previously identified CR for subjects where the intervening integrated 
responses, up to three (3), were NE. Subsequent documentation of PR may provide confirmation 
of a previously identified PR for subjects where the intervening integrated responses, up to three 
(3), were NE. If the post-NE TPR confirms the CR (or PR) then the Confirmed Response will be 
CR (or PR). For example, CR NE CR = confirmed CR, CR NE NE CR = confirmed CR, or CR 
NE NE NE CR = confirmed CR ; PR NE PR = confirmed PR, PR NE NE PR = confirmed PR, or 
PR NE NE NE PR = confirmed PR ; CR SD C 
Note: in the following scenario, PR SD NE PR, the second PR is not a confirmed PR. 
(1) TPR is SD if the increase from the first to the second assessment does not qualify for PD. 
 
The confirmed response (best response) is defined when all Overall response assessments have 
been reviewed. 
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