A Compassionate Use Study of Leronlimab (PRO 140) Plus Treatment of Physician's Choice in Patients With CCR5+ Metastatic Triple Negative Breast Cancer (mTNBC)
Conditions: Metastatic Triple-Negative Breast Carcinoma
Sponsor: CytoDyn, Inc.

 
 
CytoDyn Inc.    1111 Main Street, Suite 660, Vancouver, Washington 98660   T 360.980.8524  F 360.799.5954 
 
 
Protocol Cover Page 
 
 
Protocol Title: A Compassionate Use Study of Leronlimab (PRO 140) plus Treatment of 
Physician’s Choice in Patients with CCR5+ Metastatic Triple-Negative Breast Cancer (mTNBC) 
 
Protocol Number: CD07_TNBC_CompassionateUse 
 
Version: 4.0 
 
Document Date: 14-May-2020 
 
NCT Number: NCT04313075 
 

 
 
CONFIDENTIAL 
 
  
 
Page 1 of 127 
 
 
A Compassionate Use Study of Leronlimab (PRO 140) plus Treatment of 
Physician’s Choice in Patients with CCR5+ Metastatic Triple-Negative Breast 
Cancer (mTNBC) 
 
Protocol Number: 
CD07_TNBC_CompassionateUse 
Version: 
4.0 
Date: 
14-May-2020 
 
 
Sponsor: 
CytoDyn, Inc. 
1111 Main Street, Suite 660 
Vancouver, Washington 98660 
(360) 980-8524-Work 
(360) 980-8549-Fax 
www .cytodyn.com 
Lead Principal Investigator: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is a confidential communication of CytoDyn, Inc. It is provided for the conduct of a 
clinical research study. The information contained in this document is confidential and, except to the 
extent necessary to obtain informed consent or IEC/IRB approval, cannot be disclosed unless required by 
governmental regulation. Persons to whom any portion of the contents of this document is disclosed must 
be informed that the information is confidential and may not be further disclosed by them. 

 
 
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PROTOCOL APPROVAL PAGE 
 
 
 
 
Protocol Number:  
CD07_TNBC_CompassionateUse 
 
Version: 
 
4.0 
 
Date: 
 
14-May-2020 
We, the undersigned, have reviewed this protocol and agree that it contains all relevant information 
required to meet FDA, GCP and all applicable regulatory guidelines and statutes. 
PROTOCOL APPROVAL FOR USE 
 
 
 
 
 
 
  
  
 
Date 
 
 
 
 
  
 
  
 
 
 
Date 
 
 
 
 
  
 
  
 
 
Date 
 
 
 
  
 
 
  
 
  
  
 
 
 
 
Date 
 
 
 
 
 
Date 

 
 
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INVESTIGATOR’S SIGNATURE PAGE 
 
 
 
Protocol Number:  
CD07_TNBC_CompassionateUse 
 
Version: 
 
4.0 
 
Date: 
 
14-May-2020 
 
I have read the protocol specified above and agree to participate in and comply with the procedures, as 
outlined herein for the conduct of this clinical trial. I also agree to comply with US Food and Drug 
Administration (FDA) regulations and Investigational Review Board/Institutional Ethics (IRB/IEC) 
requirements for testing on human subjects. I agree to ensure that the requirements for obtaining informed 
consent are met.  
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
Date 
Print Name 
 
 
 
 
 
 
Site Number 
 
 
 

 
 
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SPONSOR INFORMATION 
CytoDyn, Inc. 
1111 Main Street, Suite 660 
Vancouver, Washington 98660 
(360) 980-8524-Work 
(360) 980-8549-Fax 
www .cytodyn.com 
 
 
 
CONTRACT RESEARCH ORGANIZATION INFORMATION 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ..............................................................................................................5 
TABLE OF CONTENTS ............................................................................................................13 
List of Tables .................................................................................................................................19 
List of Figures ...............................................................................................................................20 
List of Abbreviations .....................................................................................................................21 
1 INTRODUCTION AND BACKGROUND .........................................................................24 
1.1 
Statement of Intent ..............................................................................................................24 
1.2 
Background of the Disease ..................................................................................................24 
1.2.1. 
Triple Negative Breast Cancer (TNBC) ............................................................24 
1.2.2. 
C-C Chemokine Receptor Type-5 (CCR5) .......................................................24 
1.2.3. 
Circulating Tumor Cells (CTCs) in Metastatic Breast Cancer (MBC) .............27 
1.2.4. 
CCR5+ Tumor-Infiltrating Leukocytes .............................................................27 
1.3 
Study Treatments .................................................................................................................31 
1.3.1. 
Leronlimab (PRO 140) ......................................................................................31 
1.4 
Pre-Clinical Studies of leronlimab (PRO 140) ....................................................................31 
1.4.1. 
Effect of PRO140 on human CCR5 in breast cancer cells, MDA-MB-231......32 
1.4.1.1 
PRO140 binding to human CCR5 in human breast cancer cells .......................32 
1.4.1.2 
PRO140 blocks human CCR5 mediated signaling in human breast cancer cells.33 
1.4.1.3 
PRO140 blocks human CCR5 mediated invasion of extracellular matrix in 
human breast cancer cells. .................................................................................34 
1.4.2. 
Effect of PRO 140 on Growth of SW480 Human Colon Carcinoma Xenografts36 
1.4.3. 
Clinical Studies with leronlimab (PRO 140) .....................................................39 
1.4.4. 
PRO 140 1101 Study .........................................................................................39 
1.4.5. 
PRO 140 1102 Study .........................................................................................39 
1.4.6. 
PRO 140 1103 Study .........................................................................................40 
1.4.7. 
PRO 140 1302 Study .........................................................................................40 
1.4.8. 
PRO 140 2301 Study .........................................................................................40 
1.4.9. 
PRO 140 2101 Study .........................................................................................41 
1.4.10. 
PRO 140_CD01 Study ......................................................................................41 
1.4.11. 
PRO 140_CD01 Extension Study .....................................................................42 

 
 
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1.4.12. 
PRO 140_CD02 Study ......................................................................................43 
1.4.13. 
PRO 140_CD02 Extension Study .....................................................................44 
1.4.14. 
PRO 140_CD03 HIV Study ..............................................................................44 
1.4.15. 
PRO 140_CD03 HIV Extension Study .............................................................45 
1.4.16. 
PRO 140_CD06 Study ......................................................................................45 
1.4.17. 
PRO 140_CD07 Study ......................................................................................45 
1.4.18. 
CD08_mCRC Study ..........................................................................................45 
1.5 
Study Rationale ...................................................................................................................48 
1.5.1. 
Rationale for Target Population ........................................................................48 
1.5.2. 
Rationale for Dose Selection .............................................................................49 
1.6 
Risks / Benefits Assessment ................................................................................................50 
1.6.1. 
Risks/Discomfort to Subjects and Precautions to Minimize Risk .....................50 
1.6.2. 
Intended Benefit for Subjects ............................................................................51 
2 STUDY OBJECTIVES ..........................................................................................................53 
3 STUDY DESIGN ....................................................................................................................54 
3.1 
Study Center ........................................................................................................................55 
3.2 
Study Population .................................................................................................................55 
3.3 
Eligibility Criteria ................................................................................................................55 
3.3.1. 
Inclusion Criteria ...............................................................................................55 
3.3.2. 
Exclusion Criteria ..............................................................................................57 
4 STUDY SCHEDULE .............................................................................................................59 
4.1 
Pre-Screening Period ...........................................................................................................65 
4.1.1. 
Pre-Screening Visit............................................................................................65 
4.2 
Screening Period ..................................................................................................................66 
4.2.1. 
Screening Visit (SV) .........................................................................................66 
4.3 
Treatment Period .................................................................................................................67 
4.3.1. 
Treatment Period, T1 (Week 1) .........................................................................67 
4.3.2. 
Treatment Period, T2 (Week 2) Onward ...........................................................68 
4.4 
Follow-Up Period ................................................................................................................69 
4.4.1. 
End of Treatment Visit (EOT)...........................................................................69 
4.4.2. 
Survival Follow-up Visits .................................................................................70 

 
 
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4.5 
Unscheduled Visits ..............................................................................................................71 
5 SUBJECT COMPLETION, WITHDRAWAL AND CRITERIA FOR STOPPING THE 
STUDY ....................................................................................................................................72 
5.1 
Removal of Subjects from Study Treatment and/or Study as a Whole ...............................72 
5.2 
Data Collected from Withdrawn Subjects ...........................................................................73 
5.3 
Screen Failures ....................................................................................................................73 
6 STUDY TREATMENT .........................................................................................................74 
6.1 
leronlimab (PRO 140) .........................................................................................................74 
6.1.1. 
Leronlimab (PRO 140) – Packaging and Labeling ...........................................75 
6.1.2. 
Leronlimab (PRO 140) – Storage and Handling ...............................................76 
6.1.3. 
Leronlimab (PRO 140) – Administration ..........................................................76 
6.1.4. 
Leronlimab (PRO 140) – Post Injection Monitoring.........................................77 
6.1.5. 
Leronlimab (PRO 140) – Dose Modifications ..................................................77 
6.1.6. 
Leronlimab (PRO 140) – Disposition ...............................................................78 
6.1.7. 
Leronlimab (PRO 140) – Accountability ..........................................................78 
6.1.8. 
Return and Retention of Study Drug .................................................................79 
7 DESCRIPTION OF PROTOCOL ASSESSMENTS AND PROCEDURES ...................80 
7.1 
Informed Consent ................................................................................................................80 
7.2 
Assessment of Eligibility .....................................................................................................80 
7.2.1. 
Re-screening ......................................................................................................80 
7.3 
Demographic Information and Baseline Disease Characteristics .......................................80 
7.4 
Medical History ...................................................................................................................81 
7.5 
Concomitant Medication .....................................................................................................82 
7.5.1. 
Permitted Medications .......................................................................................82 
7.5.2. 
Prohibited Medications......................................................................................83 
7.6 
Vital Signs, Height and Weight ...........................................................................................83 
7.7 
Physical Examination ..........................................................................................................83 
7.8 
ECOG Performance Status ..................................................................................................84 
7.9 
Electrocardiogram (ECG) ....................................................................................................84 
7.10 Toxicity Assessment ............................................................................................................85 

 
 
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7.11 Clinical Laboratory Assessments ........................................................................................85 
7.11.1. 
Correlatives/Special Studies ..............................................................................86 
7.11.1.1 
Sample Collection Guidelines ...........................................................................87 
7.11.1.2 
Sample Processing, Storage, and Shipment ......................................................87 
7.11.1.3 
Assay Methodology ...........................................................................................88 
7.12 Study Treatment Application ..............................................................................................89 
7.13 Post-Injection Evaluation and Injection Site Reaction Assessment ....................................89 
7.14 Pain Assessment using Visual Analog Scale (VAS) ...........................................................89 
7.15 Tumor Imaging and Response Evaluation ......................................................................8991 
7.15.1. 
Definition of Lesions .....................................................................................9091 
7.15.2. 
Method of Assessment ..................................................................................9293 
7.15.3. 
Baseline documentation of ‘target’ and ‘non-target’ lesions ........................9293 
7.15.4. 
Evaluation of target lesions ...........................................................................9394 
7.15.5. 
Evaluation of non-target lesions ....................................................................9495 
7.15.6. 
9596 
7.15.7. 
Evaluation of Best Overall Response ............................................................9596 
7.15.8. 
Duration of Response ....................................................................................9697 
7.16 Survival Status .................................................................................................................9697 
7.17 Treatment of Physician’s Choice ....................................................................................9697 
8 STATISTICAL ANALYSIS .............................................................................................9899 
8.1 
Treatment Groups ............................................................................................................9899 
8.2 
Sample Size Determination and Rationale ....................................................................99100 
8.3 
Randomization and Stratification ..................................................................................99100 
8.4 
Blinding .........................................................................................................................99100 
8.5 
Interim Analysis ............................................................................................................99100 
8.6 
Statistical Considerations ..............................................................................................99100 
8.6.1. 
Analysis Populations ...................................................................................99100 
8.6.1.1 
Evaluable Population ...................................................................................99100 
8.6.1.2 
Per Protocol Population ...............................................................................99100 
8.6.1.3 
Safety Population ........................................................................................99100 
8.6.2. 
Covariates ..................................................................................................100101 

 
 
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8.6.3. 
Missing Data..............................................................................................100101 
8.7 
Analysis Methods ........................................................................................................100101 
8.7.1. 
Subject Disposition....................................................................................100101 
8.7.2. 
Demographic and Baseline Disease Characteristics .................................100101 
8.7.3. 
Study Analyses ..........................................................................................100101 
8.7.3.1 
Safety Analyses .........................................................................................103104 
9 ADVERSE EVENTS (DEFINITIONS AND REPORTING) ....................................105106 
9.1 
Adverse event (AE) .....................................................................................................105106 
9.2 
Reporting and Follow-Up of Adverse Events .............................................................105106 
9.2.1. 
Impact on Study Treatment .......................................................................105106 
9.2.2. 
CTCAE Grade (Intensity) Assessment......................................................105106 
9.2.3. 
Causality Assessment ................................................................................106107 
9.2.4. 
Treatment Given as a Result of the Event .................................................107108 
9.2.5. 
Outcome Assessment ................................................................................107108 
9.2.6. 
Injection-site reactions ..............................................................................107108 
9.3 
Serious Adverse Events ...............................................................................................107108 
9.4 
Reporting of Serious Adverse Events .........................................................................108109 
9.5 
SAE Follow-Up ...........................................................................................................108109 
10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ..............................109110 
11 QUALITY CONTROL AND QUALITY ASSURANCE ...........................................110111 
11.1 Monitoring Requirements ............................................................................................110111 
11.2 Acceptability of Case Report Forms (CRFs) ..............................................................110111 
11.3 Modification of Protocol .............................................................................................111112 
11.4 Reporting Protocol Deviations ....................................................................................111112 
11.4.1. 
Major Protocol Deviation or Violation .....................................................111112 
11.4.2. 
Minor Protocol Deviation or Violation .....................................................112113 
12 DATA SAFETY MONITORING BOARD (DSMB) ..................................................113114 
13 ETHICS AND REGULATORY REQUIREMENTS .................................................115116 
13.1 Institutional Review Board/Independent Ethics Committee (IRB/IEC) .....................115116 
13.2 Investigator’s Responsibilities ....................................................................................115116 

 
 
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13.3 Subject Informed Consent Requirements ....................................................................116117 
14 DATA HANDLING AND RECORD KEEPING ........................................................117118 
14.1 Recording and Collection of Data ...............................................................................117118 
14.2 Clinical Data Management ..........................................................................................117118 
14.3 Archiving .....................................................................................................................118119 
15 PUBLICATION PLAN .................................................................................................120121 
16 REFERENCES ...............................................................................................................121122 
17 APPENDIX .....................................................................................................................125126 
17.1 Appendix 1:  Acceptable methods of Contraception ...................................................125126 
17.2 Appendix 2: Recommendations for HER-2 testing in breast cancer ...........................126127 
17.3 Appendix 3: Common Terminology Criteria for Adverse Events v5.0 ......................127128 

 
 
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LIST OF TABLES 
Table 1-1: 
List of Completed Clinical Studies with leronlimab (PRO 140) .............................46 
Table 1-2: 
List of Ongoing Clinical Studies with leronlimab (PRO 140) ................................47 
Table 4-1: 
Schedule of Assessments .........................................................................................61 
Table 6-1: 
Treatment Administration Summary .......................................................................74 
Table 6-2: 
Investigational Product – leronlimab (PRO 140) ....................................................74 
Table 6-3: 
Leronlimab (PRO 140) Dose Modification and Management for Injection Site 
Reactions .................................................................................................................78 
Table 7-1: 
ECOG Performance Status Scale ............................................................................84 
Table 7-2: 
Central Lab Parameters ...........................................................................................86 
Table 7-3: 
Target Lesion Evaluation ....................................................................................9394 
Table 7-4: 
Non-Target Lesion Evaluation ............................................................................9495 
Table 7-5: 
Time point response: subjects with target (± non-target) disease .......................9596 
Table 9-1:  
CTCAE v5.0 General Guidelines ....................................................................106107 
 

 
 
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LIST OF FIGURES 
Figure 1-1: 
CCR5 over-expression correlates with poor survival). Immunohistochemical 
staining for CCR5 in 537 patients ...........................................................................25 
Figure 1-2: 
The CCR5 antagonist Maraviroc inhibits lung metastases in vivo .........................26 
Figure 1-3: 
Tumor Tregs (Stain with CD4, CD325, CD127, and CCR5) ..................................28 
Figure 1-4: 
IHC staining showing high predominance of CCR5+ tumor infiltrating leukocytes 
in TNBC (Subject 1) ................................................................................................29 
Figure 1-5: 
IHC staining showing high predominance of CCR5+ tumor infiltrating leukocytes 
in TNBC (Subject 2) ................................................................................................30 
Figure 1-6: 
 PRO-140 binds human CCR5 in human breast cancer cells. .................................32 
Figure 1-7: 
 PRO140 blocks human CCR5 mediated signaling in human breast cancer cells. .34 
Figure 1-8: 
 PRO140 blocks CCL5-induced breast cancer cell invasion ...................................35 
Figure 1-9: 
 Part 1: SW480 Human Colon Carcinoma Xenografts Grown in NCr Nude Mice .37 
Figure 1-10:  Part 2: SW480 Human Colon Carcinoma Xenografts Grown in NCr Nude Mice .38 
Figure 1-11:  Part 3: SW480 Human Colon Carcinoma Xenografts Grown in NCr Nude Mice .38 
Figure 1-12:  Part 4: SW480 Human Colon Carcinoma Xenografts Grown in NSG Mice .........39 
Figure 3-1: 
Study Schematic ......................................................................................................54 
Figure 4-1: 
Study Flow Diagram ...............................................................................................60 
Figure 6-1: 
Investigational Product – Vial Label .......................................................................75 
Figure 6-2: 
Investigational Product – Syringe Label .................................................................75 
Figure 6-3: 
Investigational Product – Kit Label .........................................................................76 
Figure 7-1: 
Visual Analog Scale ............................................................................................8990 

 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CAML 
Cancer-Associated Macrophage-Like cell 
Cmax 
Maximal Concentration 
cART 
Combination Antiretroviral Therapy 
CBR 
Clinical Benefit Rate 
CCL5 
C-C Chemokine Ligand Type-5 
CCR5 
C-C Chemokine Receptor Type-5 
CFR 
Code of Federal Regulations 
CHO 
Chinese Hamster Ovary 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
CTC 
Circulating Tumor Cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAPI 
4,2-diamidino-2- phenylindole dihydrochloride  
DFS 
Disease Free Survival 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECL2 
ExtraCellular Loop 2 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
ER 
Estrogen Receptor 
FDA 
U.S. Food and Drug Administration 
FI 
Fluorescent Intensity   

 
 
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Abbreviation 
Term 
FISH 
Fluorescence in Situ Hybridization 
FOCBP 
Females of Child-bearing Potential 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HDR 
Homology-Directed DNA Repair 
HEENT 
Head, Ears, Eyes, Nose, and Throat 
HER2 
Human Epidermal Growth Factor Receptor-2 
HIPAA 
Health Insurance Portability Accountability Act 
HIV-1 
Human Immunodeficiency Virus Type 1 
IA 
Interim Analysis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry assay 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISR 
Injection Site Reactions 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LAR 
Legally Authorized Representative 
LTF 
Lost to Follow-up 
mAb 
Monoclonal Antibody 
mCRC 
Metastatic Colorectal Cancer 
MSS 
Microsatellite Stable 
MTD 
Maximum Tolerate Dose 
Nt 
N terminus 
OBT 
Optimized Background Therapy 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OTC 
Over the Counter 
PFS 
Progression Free Survival 

 
 
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Abbreviation 
Term 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Progesterone Receptor 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Stable Disease 
SLD 
Sum of the Longest Diameters 
SOP 
Standard Operating Procedure 
SV 
Screening Visit 
TEAE 
Treatment Emergent Adverse Event 
TNBC 
Triple Negative Breast Cancer 
TTNM 
Time to New Metastasis 
VAS 
Visual Analog Scale 
VF 
Virologic Failure 

 
 
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1 INTRODUCTION AND BACKGROUND 
1.1 
STATEMENT OF INTENT 
The design, conduct and reporting of this study shall be conducted in compliance with the 
protocol, International Conference on Harmonization/Good Clinical Practice (ICH/GCP), and all 
appropriate regulatory requirements. Investigator(s) participating in this study will have 
documented training in GCP. Independent monitoring of the trial will be accomplished utilizing a 
Contract Research Organization (CRO). 
1.2 
BACKGROUND OF THE DISEASE 
1.2.1. Triple Negative Breast Cancer (TNBC) 
Clinical and molecular heterogeneity of breast cancer are translated in a diversity of clinical 
patterns of disease evolution and patient outcomes [Dawood, 2011] [Engstrom, 2013] [Harbeck, 
2016]. TNBC is defined by the lack of estrogen receptor (ER), progesterone receptor (PgR) and 
human epidermal growth factor receptor-2 (HER-2) expression, which are known targets of 
endocrine therapies and anti-HER2 agents, respectively. Chemotherapy is still the main treatment 
option for TNBC patients. It accounts for 15-20% of breast cancer patients, a clinically highly 
relevant patient group that is characterized by younger age, unfavorable histopathological features 
including high histological grade, elevated mitotic count, high rate of p53 mutations and pushing 
margins of invasion with a shortened overall survival (OS) and disease free survival (DFS) 
compared to other breast cancer subgroups [Dawood, 2011] [Engstrom, 2013][Malorni, 2012]. 
For these reasons, TNBC account for a disproportionately high percentage of metastases, 
particularly distant recurrence, and death among patients with breast cancer. Moreover, in 
younger women TNBC has been described to occur more often with a high risk of recurrence and 
death, respectively, the latter with a peak incidence of 3 years after primary diagnosis. The pattern 
of recurrence involves more often visceral organs and less common bones compared to other 
breast cancer subtypes [Foulkes, 2010]. 
1.2.2. C-C Chemokine Receptor Type-5 (CCR5) 
The process of cancer cell metastasis in different organs is a complex biologic event. Each tumor 
type presents a unique pattern of dissemination that has been well recognized for over a century 
as the “soil and seed” hypothesis [Paget, 1889]. However, only recently factors involved in this 
process have started to be understood. Preclinical and clinical data have suggested that chemokine 
receptors and its ligands, also referred as chemoattractant or chemotactic cytokines, are involved 
in the process of cancer cells tropism by specific organs [Moser, 2001][Neagu, 2015][Velasco-
Velazquez, 2012][Chow, 2014]. Studies have correlated the altered expression of C-C Chemokine 
Ligand type-5 (CCL5) with disease progression in patients with breast cancer [Luboshits, 

 
 
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1999][Niwa, 2001][Zhang, 2009]. Immunofluorescence staining techniques are well established 
for CCR5 expression. Velasco-Velazquez et al have evaluated an analysis of a combined 
microarray database comprising 2,254 breast cancer samples and showed that expression of 
CCL5/CCR5 is higher in basal subtypes (over 58% of samples) of breast cancer compared to 
luminal subtypes [Velasco-Velazquez, 2012]. 
Figure 1-1: 
CCR5 over-expression correlates with poor survival). Immunohistochemical 
staining for CCR5 in 537 patients 
 
 
CCR5 is also associated with programmed death-ligand 1 (PD-L1) [Halama, 2016]. Anti-PD-L1 
antibodies have shown outstanding efficacy in the clinic for melanoma, non-small cell lung 
cancer and other cancers [Moser, 2001] [Garon, 2015] [Borghaei, 2015][Brahmer, 2015][Larkin, 
2015]. Upregulation of PD-L1 may allow cancers to evade the host immune system and also 
inducing apoptosis in activated T cells. Preclinical data have shown that PD-L1 present in cancer 
is correlated with CCR5 abundance. Thus, blocking CCR5 may also contribute to increased 
immune response against tumor cells.  
CCR5 has been shown to be sufficient to induce in vitro invasiveness and metastasis of breast 
cancer cells that is blocked by CCR5 inhibitors. Two distinct CCR5 inhibitors (Maraviroc, 
Vicriviroc) blocked CCR5 signaling and thereby blocked cells migration, invasion and metastasis 
in mice (Figure 1-2Figure 1 2) [Velasco-Velazquez]. The CCR5 inhibitors were shown to block 
homing of breast cancer cells to the lungs. The dose of CCR5 inhibitor used in these mouse 
models was the same as the dose used in patients for HIV treatment. Preclinical studies have also 
demonstrated that oncogenic transformation of immortal human breast cancer cells, with either 
Ha-Ras, c-Myc, ErbB2 (NeuT) or c-Src, induces the mRNA expression and protein abundance of 
CCR5 during the process of transformation [Velasco-Velazquez]. 

 
 
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Figure 1-2: 
The CCR5 antagonist Maraviroc inhibits lung metastases in vivo 
 
Another cancer hallmark that CCR5 presents potential role is the DNA repair pathways. This 
cancer characteristic attenuates apoptosis and contributes to chemotherapy resistance and tumor 
cells immortality. Preclinical data have separated CCR5+ vs CCR5- SUM159 cells by FACS and 
conducted mRNA gene expression profiling. GO term pathway analysis demonstrated CCR5+ 
cells induced the expression of pathways governing DNA repair. QT- PCR was used to quantitate 
a number of these genes and showed endogenous CCR5 enhances expression of the DNA repair 
genes, (FANCB, LIG3, POLE and CRY1) governing both homologous and non-homologous 
DNA repair, nucleotide excision repair and base excision repair. SUM159 cells stably transfected 
with CCR5 or control vector were compared for the DNA damage/repair response. Γ-radiation of 
SUM159 cells induced p-γH2AX, however CCR5-overexpressing cells showed reduced p-
γH2AX at 24 hours. Treatment of SUM159 cells with the DNA intercalating anthracycline 
doxorubicin induced γH2AX phosphorylation, and CCR5-overexpressing cells showed less p-
γH2AX than its control with 24 hours treatment. The DNA repair reporter, DR-GFP is used to 
measure homology-directed DNA repair (HDR). In order to measure HDR activity CCR5+ 
SUM159 cells, the cells were co-transfected with the plasmid encoding I-SceI and the I-SceI 
based DNA repair reporter DR-GFP and stained with APC labeled anti-CCR5 antibody. GFP+ 
cells, generated by HDR of I-SceI induced double-strand DNA, were sorted by FACS into CCR5- 
and CCR5+ populations. The percentage of DR-GFP+ cells was increased in CCR5+ or CCR5- 

 
 
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overexpressing cells compared with CCR5- or vector control cells [Robert, 2015]. The dramatic 
enhancement of DNA repair signaling by CCR5 activation may contribute to the resistance of a 
patient’s tumor to chemotherapeutic agents. 
1.2.3. Circulating Tumor Cells (CTCs) in Metastatic Breast Cancer (MBC) 
The major treatment objectives in the advanced stage disease remain palliation of symptoms and 
improvement of quality of life. Importantly, breast cancer is a heterogeneous disease and long-term 
patient outcome can be influenced by various biological features, as well as by the extent and site 
of metastatic disease. Typically, widespread visceral disease is associated with symptomatic 
progression leading to deterioration of the performance status and short survival. Various 
molecular markers and blood-based tests have been investigated as surrogate for more aggressive 
disease, among them the most reliable appears enumeration of circulating tumor cells [Xuanmao, 
2015].  
During the last decade, several techniques capable of detecting and quantifying circulating tumor 
cells (CTCs) in cancer patients have been developed. It has been proposed that subpopulation of 
CTCs with tumor initiating potential act as a central mediator of metastatic dissemination, giving 
rise to the formation of distant micrometastases, which subsequently generate overt detectable and 
frequently measurable lesions [Foulkes, 2010]. In support of this theory, multiple studies have 
shown that a number of CTCs higher or equal than 5 per 7.5 mL of blood, evaluated before 
starting systemic treatment, is associated with poor outcome in patients with metastatic breast 
cancer [Xuanmao, 2015]. In addition, high CTC counts are associated with greater metastatic tumor 
burden, expressed as number of metastatic sites [Moser,2001][Neagu, 2015]. Importantly, despite 
this association, the prognostic value of CTCs is independent from the initial number of metastatic 
sites [Moser,2001][Neagu, 2015]. Moreover, a recent pooled analysis of 1944 patients was 
performed confirming those data [Cristofanilli, 2004]. The authors created a clinicopathological 
prognostic model to determine the added impact of CTCs for PFS and OS. They found that 
adding CTC count (<5 or ≥5) to their predictive model significantly increased the prognostication 
for OS and PFS. The prognostic value of CTCs was consistent across all subtypes of disease. 
Finally, in the multivariate analysis, CTC count was the strongest prognosticator for PFS and OS. 
Furthermore, continued elevation of CTCs is known to be associated with a poor prognosis as 
well as a sign of chemoresistance [Bidard, 2014]. 
CTCs enumeration will be used as a measure of tumor cells escaping immune control and 
released into the blood. CTCs enumeration is used as a surrogate of metastasis and as a measure 
of the efficacy of therapy. CCR5 has also been implicated in the migration of tumor cell from 
blood into tissues so if CTCs are reduced by therapy but still present, a favorable result would be 
that they are no longer CCR5 positive due to receptor blockade by leronlimab. 
1.2.4. CCR5+ Tumor-Infiltrating Leukocytes 

 
 
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The role of CCR5 blockade of the CCL5-CCR5 pathway in immune control of tumors have been 
defined in several publications in the peer-reviewed medical literature [Mañes, 2003]. CCR5 on 
tumor cells especially those that evade local immune control in the primary tumor leads to CCR5 
positive circulating tumor cells that have the capability to disseminate and migrate into distant 
tumor sites again through the CCL5-CCR5 axis. Previous research and current data has also 
identified other immune mediated anti-tumor effects from CCR5 blockade [Lanitis, 2017, 
Halama, 2016]. Previous published reports suggest CCR5 expression on Treg cells which migrate 
into tumors due to the expression of CCL5 by lymphocytes [de Oliveira, 2017, Del Prete, 2017, 
Lanitis, 2017]. Tregs are responsible for minimizing or eliminating the anti-tumor effects of CD8 
T-cells now restored by blockade of PD-L1/PD-1 by the new class of immune-oncology drugs [de 
Oliveira, 2017]. Further, blocking CCR5 on tissue associated macrophages (TAMS), one of the 
major cells in the tumor microenvironment that suppresses the T-cell mediated anti-tumor 
immune response, restores the anti-tumor activity by re-programming the TAMs [Lanitis, 2017, 
Walens, 2019]. Data from novel 24-color flow cytometry assay performed on single cell 
suspensions created with IVD IncellPREP device, confirmed the expression of CCR5 on Tregs 
from the tumor microenvironment in lung, breast, and bladder cancer samples. This technology or 
CCR5 immunohistochemistry of biopsies already obtained has allowed to selectively choose 
patients with CCR5 expression not only on tumor but on intra-tumor immune cells in the tumor 
microenvironment. 
 
Figure 1-3: 
Tumor Tregs (Stain with CD4, CD325, CD127, and CCR5)  
 
 

 
 
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Because of the multitude of different mechanism CCR5 blockade may promote anti-tumor 
activity, immune control, and metastasis, the inclusion criteria has been expanded to encompass 
these varied mechanisms that may all lead to improved clinical response.  
Below are the representative IHC staining images showing high predominance of CCR5 positive 
tumor infiltrating leukocytes in Triple Negative Breast Cancer tissue samples: 
 
Figure 1-4: 
IHC staining showing high predominance of CCR5+ tumor infiltrating 
leukocytes in TNBC (Subject 1) 
 Subject 1: Representative images of IHC for CCR5 
 
 Negative Control CCR5 
 
 Positive Control CCR5 

 
 
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Figure 1-5: 
IHC staining showing high predominance of CCR5+ tumor infiltrating 
leukocytes in TNBC (Subject 2) 
 Subject 2: Representative images of IHC for CCR5 
 
 Negative Control CCR5 
 Positive Control CCR5 

 
 
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1.3 
STUDY TREATMENTS 
1.3.1. Leronlimab (PRO 140) 
Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine 
receptor type 5 (CCR5), under development as a therapy for human immunodeficiency virus 
(HIV) infection. 
Leronlimab (PRO 140) binds to the N terminus (Nt) and the extracellular loop 2 (ECL2) domain 
of the CCR5 cell surface receptor that HIV-1 uses to gain entry to a cell. Leronlimab (PRO 140) 
(binding to CCR5 blocks viral entry by interfering with the final phase of viral binding to the cell 
surface prior to fusion of the viral and cell membranes. Leronlimab (PRO 140) has been 
administered intravenously or subcutaneously to more than 750 healthy and HIV-1 infected 
individuals in Phase I/II/III studies. The drug has been well tolerated following intravenous 
administration of single doses of 0.5 to 10 mg/kg or up to 700 mg weekly doses as subcutaneous 
(SC) injection. Overall, 324 subjects have been exposed to leronlimab (PRO 140) 350 mg SC 
weekly dose with the longest duration of exposure lasting 4 years. Similarly, more than 250 and 150 
subjects have been exposed to leronlimab (PRO 140) 525 mg and 700 mg SC weekly dose, 
respectively. 
1.4 
PRE-CLINICAL STUDIES OF LERONLIMAB (PRO 140) 
In vitro and in vivo preclinical studies have been conducted to determine the pharmacokinetic, 
immunogenicity, and toxicity profiles of leronlimab (PRO 140) following IV and SC 
administration. Several acute and chronic toxicity studies have been conducted to support the 
clinical development plan.  

 
 
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Acute toxicity of leronlimab (PRO 140) was evaluated in New Zealand rabbits, following IV 
administration of 5 or 15 mg/kg. Chronic toxicity was evaluated in cynomolgus monkeys 
following biweekly administration of IV doses up to 10 mg/kg for six months and biweekly 
administration of various SC doses up to 50 mg/kg for 24 weeks. The drug was generally well 
tolerated. Biweekly administration of IV doses up to 10 mg/kg for six months resulted in 
minimum to mild lymphoid hyperplasia in assorted lymph nodes and spleen, which was 
considered an expected immune response to a foreign protein. Biweekly administration of SC 
doses up to 50 mg/kg for 24 weeks resulted in minimum injection-site reactions (minimal, 
multifocal, mononuclear cell infiltrates in the subcutis), which were considered due to an 
inflammatory response to the injected antigen. Monkeys tolerated treatment with leronlimab 
(PRO 140) for 24 weeks without evidence of local or systemic toxicity. Leronlimab (PRO 140) 
caused no mortality, cageside observations, in-life injection-site observations, or gross 
pathologic findings. Chronic treatment with leronlimab (PRO 140) did not affect body weight, 
food consumption, hematology, clinical chemistry or coagulation parameters. 
Both IV and SC administration resulted in elimination half-lives of approximately 200 hours, 
and overall exposure increased with increasing doses. Following SC administration of 
leronlimab (PRO 140) in monkeys, the maximal concentration (Cmax) was achieved within 56 
hours and bioavailability for leronlimab (PRO 140) after SC dosing was approximately 70%. 
1.4.1. Effect of PRO140 on human CCR5 in breast cancer cells, MDA-MB-231 
1.4.1.1 PRO140 binding to human CCR5 in human breast cancer cells 
Figure 1-6: 
 PRO-140 binds human CCR5 in human breast cancer cells.  
Validation of PRO140 binding to CCR5 positive cells was assessed by FACS analysis. MDA-MB-231 stably 
expressing a human CCR5 expression vector was double stained with a commercial APC-conjugated mouse anti-
human/mouse/rat CCR5 antibody and PRO140. Alexa Fluor 488 conjugated anti-human IgG was used as secondary 
antibody of PRO140. PRO 140 was diluted from 1/50 to 1/3200. (B) The efficiency of PRO140 binding to the CCR5 
positive cells. 

 
 
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In order to determine the binding of PRO140 with human CCR5 in breast cancer cells, MDA-
MB-231, a human triple-negative breast cancer cell line, was stably transfected with a human 
CCR5 expression vector as a model system. A commercial APC conjugated mouse anti-
human/mouse/rat CCR5 antibody was used as a positive control to assess CCR5 positive cells. 
MDA-MB-231-CCR5 cells were stained with both APC-αCCR5 and PRO140 using a dilution 
from 1/50 to 1/3200 (Figure 1). Alexa Fluor 488 conjugated mouse anti-human IgG was used as 
secondary antibody to measure PRO140 binding cells. Analysis of PRO140 binding with CCR5 
by FACS is shown in Figure 1. The efficiency of PRO140 binding with CCR5 was calculated as 
the ratio of Alexa Fluro 488 positive cells to APC positive cells. The efficiency of PRO140 
binding to CCR5 positive cells was 62% at 1/800 dilution (Figure 1-6Figure 1 6A, B). These 
results demonstrate that PRO140 binds with human CCR5.  
1.4.1.2 PRO140 blocks human CCR5 mediated signaling in human breast cancer cells.  
CCR5 activation induces calcium flux [Mueller, 2002][Petkovic, 2004]. To assess the effects of 
PRO140 on CCR5 function, we measured the calcium responses induced by CCL5 in MDA-MB- 
231-CCR5 cells with or without PRO140 by living cell image (Figure 1-7Figure 1 7). Fluo-4 was 

 
 
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used as calcium concentration indicator. The CCR5 antagonist, Vicriviroc, was used as a positive 
control (Figure 1-7Figure 1 7).  
MDA-MB-231-CCR5 cells were labeled with calcium indicator Fluo-4 and monitored under 
fluorescent inverted microscope with the incubator chamber at 37ºC and 5% CO2. For treated 
samples, a CCR5 inhibitor, either PRO140 or Vicriviroc, was added 30 minutes prior to the 
experiments. Video of living cells was taken at 20 sec intervals. CCL5 was added after 6 frames 
of the video, and FBS induced calcium responses were used as positive control. A representative 
example is shown in Figure 1-7Figure 1 7. Relative intracellular Ca2+ concentration was 
determined by the changes in fluorescent intensity (FI) of Fluo-4-AM and was calculated as (Fit – 
FI0)/FI0. Quantitative analysis of calcium responses induced by CCL5 are represented in Figure 
1-7Figure 1-7 (B) control, (C) PRO140, and (D) Vicriviroc. Data is shown as mean ±SEM from 
10-12 cells. 
The results showed that PRO140 can block CCL5 induced calcium responses in MDA-MB-231-
CCR5 cells at 1/100 dilution. (1.23±0.10, N=10 for control cells and 0.54±0.13 N=12 for PRO140 
treated cells. P<0.001 at calcium peak induced by CCL5). 
1.4.1.3 PRO140 blocks human CCR5 mediated invasion of extracellular matrix in human 
breast cancer cells.  
Our previous studies using CCR5 specific small molecule inhibitors demonstrated that CCR5 is 
required for the invasion of extra-cellular matrix in both breast and prostate tumor models [Sicolo, 
2014][Velasco-Velazquez, 2012]. Cancer cell invasion into the extra-cellular matrix is a key step 
of tumor metastasis [Zetter, 1990]).  
MDA-MB-231 cells were used to test the ability of PRO140 to block cell invasion in a 3D-
matrigel assay. CCL5 was used as chemoattractant to induce the invasion. Vicriviroc, a small 
molecule inhibitor of CCR5, was used as a form of positive control.  
The results showed that PRO140 can block CCL5 induced MDA-MB-231 breast cancer cell 
invasion with similar efficacy as Vicriviroc (Figure 1-8Figure 1 8A, B) (855±9, N=8 for control 
vs 855±9, N=9 for PRO140, P <0.001). We also tested the effects of different doses of PRO140 
on breast cancer cell invasion, and the results showed that both a 1/500 and a 1/1000 dilution of 
PRO140 can effectively block MDA-MB-231 cell invasion (Figure 1-8Figure 1 8C, D). Data is 
shown as mean ± SEM of the distance of cell invasion. 
Figure 1-7: 
 PRO140 blocks human CCR5 mediated signaling in human breast cancer 
cells.  
The effects of PRO140 on CCL5 induced Ca+2 responses. MDA-MB-231 stable expressing CCR5 cells was labeled 
with Calcium indicator Fluo-4 and monitored under fluorescent inverted microscope with incubator chamber at 37oC 
and 5% CO2. Video of living cells was taken with 20 sec intervals. 30 minutes prior to the experiments, PRO140 or 
Vicriviroc was added. CCL5 was added after 6 frames of the video and FBS induced calcium responses were used as 

 
 
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a positive control. A representative example is shown. (B-D) quantitative analysis of calcium responses induced by 
CCL5 in control (B), PRO140 (C) or Vicriviroc (D) treated cells. Data is shown as mean ±SEM from 10-12 cells. 
 
Figure 1-8: 
 PRO140 blocks CCL5-induced breast cancer cell invasion  
3D reconstruction of CCL5-induced invasion into collagen I gels by MDA-MB-231 breast cancer cells in presence of 
PRO140. CCL5 was used as chemoattractant. (A, B) The comparison of the effects of PRO14 and Vicriviroc. (C, D) 
The effects of different doses of PRO140 is shown. Data is shown as mean ± SEM of the distance of cell invasion. 

 
 
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1.4.2. Effect of PRO 140 on Growth of SW480 Human Colon Carcinoma Xenografts 
A study was conducted to determine the anti-tumor activity of PRO 140 humanized monoclonal 
antibody against CCR5 in mouse xenograft models of SW480 human colon carcinoma grown in 
immunocompromised mice. The study was conducted in four parts, using different mouse strains, 
drug doses, and drug schedules.  
SW480 human colon carcinoma cells (ATCC) were expanded in culture (DMEM, 10%FBS, 
antibiotic, antimycotic) and were inoculated subcutaneously (2 million per site, s.c.) in the flanks 
of male NCr nu/nu mice (Taconic), and male NOD-scid-IL2Rg (NSG) mice (Jackson). Mice were 
randomized to receive Control human IgG or PRO 140 intraperitoneal injection (i.p.) twice per 
week (Mon, Thu). Tumor diameters were measured 3 times weekly (Mon, Wed, Fri) with 
calipers, and tumor volume calculated using the formula for a prolate spheroid. The body weight 
of mice was determined weekly (Wed).  

 
 
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In Part 1 (high dose, early Rx) of the study, 2 mg PRO 140 i.p. was administered twice weekly, 
starting at Day 1 in 16 athymic nude mice. Part 2 (high dose, late Rx) included 8 athymic nude 
mice receiving 2 mg PRO140 i.p administered twice weekly, beginning Day 21. 
In Part 3 (low dose, early Rx), 0.2 mg PRO 140 i.p was administered, beginning on Day 1, twice 
weekly in 16 athymic nude mice. Lastly, in Part 4 (high dose, early Rx), 16 NSG mice received 2 
mg PRO 140 i.p, twice weekly, beginning Day 1. 
PRO 140 dosage was calculated using “Representative Surface Area to Weight Ratios (km) for 
Various Species” from: Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE. Quantitative 
comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man, 
Cancer Chemother Rep. 1966;50:219-44; and the National Cancer Institute Developmental 
Therapeutics Program http://dtp.nci.nih.gov  
Starting with the human dose of PRO 140 = 5.8 mg/kg x 12 (man-to-mouse conversion factor) = 
69.6 mg/kg mouse dose. Average mouse = 0.025 kg, therefore 69.6 mg/kg x 0.025 kg = 1.74 mg 
(mouse single dose). This was rounded up to 2.0 mg and designated as the high dose. A low dose 
(0.2 mg) was also tested. As control antibody, IgG derived from human serum was used (>95% 
SDS-PAGE, Sigma, I4506). 
In Part 1, administration of PRO 140 (2 mg i.p. twice a week) induced a 62.8% reduction in 
SW480 tumor volume by day 42 (p=0.014). Mice receiving PRO 140 exhibited normal weight 
gain over the course of the study, whereas mice receiving non-specific IgG lost weight during the 
second half of the study (p=0.047). 
Figure 1-9: 
 Part 1: SW480 Human Colon Carcinoma Xenografts Grown in NCr Nude 
Mice 
 PRO 140 2 mg i.p. Twice/Wk, Started Day 1, n=16 Tumors/Group 
 
 

 
 
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During Part 2, treatment of larger established tumors (volume: Cont 68.5 ± 47.25, PRO 140 47.25 
± 34.89 mm3) with PRO 140 (2 mg i.p. twice a week) commencing on day 21, did not result in 
significant inhibition of tumor growth (p=0.719). 
Figure 1-10:  Part 2: SW480 Human Colon Carcinoma Xenografts Grown in NCr Nude 
Mice 
PRO 140 (2 mg i.p. Twice/Wk), Started Late (D21), n= 8 Tumors/Group 
 
In Part 3 of the study, administration of PRO 140 at a reduced dose (0.2 mg i.p. twice a week) 
induced an 18.3% reduction in SW480 tumor volume by day 42, but did not reach statistical 
significance (p=0.272). During tumor progression in the second half of the study, both groups 
exhibited similar degree of weight loss (p=0.708). 
Figure 1-11:  Part 3: SW480 Human Colon Carcinoma Xenografts Grown in NCr Nude 
Mice 
 PRO 140 0.2 mg i.p. Twice/Wk, Started Day 1, n=16 Tumors/Group 
 

 
 
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For Part 4, switching from nude mice (lack T cells) to a more immunosuppressed host (NSG lack 
T, B, NK cells) resulted in loss of PRO 140 anti-tumor efficacy. There was a 32% reduction in 
tumor volume in the PRO 140 groups compared to control, but this did not reach statistical 
significance (p=0.076). There was a similar degree of weight loss in both treatment groups 
(p=0.61). 
Figure 1-12:  Part 4: SW480 Human Colon Carcinoma Xenografts Grown in NSG Mice  
PRO 140, 2 mg i.p. Twice/Wk Started Day 1, n=16Tumors/Group 
1.4.3. Clinical Studies with leronlimab (PRO 140) 
Current human experience with leronlimab (PRO 140) consists of nine completed and six 
ongoing clinical trials, mostly on healthy subjects or HIV-1 positive subjects. These studies are 
summarized in Table 1-1Table 1 1 and Table 1-2Table 1 2 (pages 46-47). In all clinical trials, 
the majority of adverse events (Aes) have been mild or moderate. No dose-limiting toxicities or 
patterns of drug-related toxicities were observed. Antiviral activity was potent, rapid, prolonged, 
dose-dependent, and highly significant. 
1.4.4. PRO 140 1101 Study 
For the first-in-human trial, PRO 140 1101, the drug was administered IV at 0.1, 0.5, 2.0, or 5.0 
mg/kg to healthy subjects and was generally well tolerated, non-immunogenic, and without 
clinically relevant toxicity. Treatment Emergent Adverse Events (TEAEs) did not increase with 
rising PRO 140 dose levels. Seventy-five percent (75%) of subjects reported TEAEs, most of 
which were deemed unrelated to study treatment by the investigator. 
1.4.5. PRO 140 1102 Study 
For PRO 140 1102, the majority of Aes, other than injection-site reactions, were considered mild 
and possibly related to drug administration. The majority of injection-site reactions were 
considered mild, self-resolving, and definitely related to drug administration. PRO 140 derived 

 
 
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from Chinese Hamster Ovary (CHO) cells and administered at 100 mg/mL was generally well 
tolerated in healthy, normal volunteers. Overall, PRO 140 administered SC using Autoject® 2 
appeared better tolerated than manual injection. 
1.4.6. PRO 140 1103 Study  
In PRO 140-1103, administration of PRO 140 at 350 mg using Autoject® 2 appeared well 
tolerated. Manual injections, on the other hand, were associated with a greater number of Aes. 
There did not appear, however, to be any substantial difference in subject perception of pain or 
discomfort related to site of drug administration. No anti-PRO 140 antibodies were detected in 
any subjects in this study. There was a tendency of higher exposure associated with SC 
administration of PRO 140 at 350 mg in the abdomen and the thigh. A higher number of Aes were 
associated with injections in the arm. Based on these observations, thigh and abdominal 
administration of PRO 140 were preferred over arm injection. 
1.4.7. PRO 140 1302 Study 
The initial proof-of-concept study was a randomized, double-blind, placebo-controlled study in 
subjects with early-stage, asymptomatic HIV infection, only R5 HIV-1 detectable, and no 
antiretroviral therapy for 12 weeks [Jacobson, 2008]. Subjects (n=39) were randomized to receive 
a single IV injection of placebo or PRO 140 at doses of 0.5, 2, or 5 mg/kg. Subjects were 
monitored for antiviral effects, safety, and PRO 140 pharmacokinetics (PK) for 58 days.  
PRO 140 demonstrated potent, rapid, prolonged, and dose-dependent antiviral activity. 
Intravenous PRO 140 was generally well tolerated. No drug-related serious events or dose-
limiting toxicity was observed [Jacobson, 2008]. The most common adverse events (headache, 
lymphadenopathy, diarrhea, and fatigue) were observed at similar frequencies across the placebo 
and PRO 140 dose groups. There was no significant effect on QTc intervals or other 
electrocardiographic parameters, and there were no remarkably laboratory findings. 
1.4.8. PRO 140 2301 Study 
PRO 140 2301 was a multi-center, randomized, double-blind, placebo-controlled, parallel group 
study in 30 male and female adult subjects infected with HIV-1 [Jacobson, 2010]. Subjects were 
randomized to one of three groups (N=10/group), each receiving one of three treatments: (i) a 
single IV dose of 5 mg/kg by 30-minute IV infusion; (ii) a single IV dose of 10 mg/kg by 30-
minute IV infusion; (iii) a single placebo dose by 30-minute IV infusion. The objective of the 
study was to assess and characterize the PK and PD of PRO 140 administered by IV infusion, 
assess efficacy at a new dosage level, and safety and tolerability of single doses of PRO 140. 
All PRO 140-treated subjects had more than 10-fold reduction in viral loads [Jacobson, 2010]. 
Both the 5 mg/kg and 10 mg/kg doses have shown favorable tolerability and no dose-limiting 

 
 
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toxicity has been observed. High levels of receptor occupancy (>85% reduction in the number of 
cells detected) were observed for 29 days after treatment with both 5 and 10 mg/kg doses.  
1.4.9. PRO 140 2101 Study 
A subcutaneous (SC) form of PRO 140 was tested in HIV-infected subjects. The trial was a 
randomized, double-blind, placebo-controlled study in subjects (n=44) with early-stage, 
asymptomatic HIV infection, only R5 HIV-1 detectable, and no antiretroviral therapy for 12 
weeks [Thompson, 2009]. Placebo (n=10) and three PRO 140 doses were examined: 162 mg 
weekly for three weeks (n=11), 324 mg weekly for three weeks (n=11), and 324 mg biweekly 
(every other week) for two doses (n=12). Subjects were followed for 44 days after the final dose.  
Potent, dose-dependent and highly statistically significant antiviral activity was observed. The 
trial established the first antiviral proof of concept for a long-acting, self-administrable drug for 
HIV-1 infection [Thompson, 2009]. 
Subcutaneous PRO 140 was generally well tolerated both locally and systemically. There was no 
obvious dose-related pattern of toxicity. The most common adverse events (diarrhea, headache, 
lymphadenopathy and hypertension) were mild to moderate and self-resolving. These events are 
common in HIV infection and were reported with similar frequencies in the placebo and PRO 140 
treatment groups. Administration-site reactions were mild, transient, and observed in a fraction of 
subjects.  
1.4.10. PRO 140_CD01 Study 
PRO 140_CD01 study (open-label, 43 subjects, multi-center) evaluated the efficacy, safety, and 
tolerability of PRO 140 monotherapy (350 mg subcutaneous injection weekly for up to 12 weeks) 
for the maintenance of viral suppression following substitution of antiretroviral therapy in HIV-1 
infected patients (with exclusive CCR5-tropic virus). Participants in this study were experienced 
HIV-infected individuals who were virologically suppressed on combination antiretroviral 
therapy. Consenting patients were shifted from combination antiretroviral regimen to PRO 140 
monotherapy for 12 weeks.  
Forty-three (43) subjects (M/F: 37/3) with median age of 54.5 years (26-72) and median CD4 T-
cell count of 604.5 cells/mm3 (365-1240) were enrolled in the CD01 study. Overall, twenty-two 
out of 40 (55%) enrolled subjects completed 12 weeks of PRO140 monotherapy without 
experiencing virologic failure. Virologic failure was defined as two consecutive HIV-1 RNA 
levels of ≥ 400 copies/mL separated by at least 3 days. Of the 43 enrolled subjects, 3 subjects 
were found to have Dual/Mixed (D/M) tropism [1 at baseline and 2 at the time of virologic 
failure] and 37 subjects were found to have exclusive CCR5-tropic virus. A letter of amendment 
was filed to increase the planned number of subjects from 40 to 43 subjects to compensate for the 
3 Dual/Mixed subjects enrolled in the study. 

 
 
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All virologic failure subjects who had available lab data in both studies achieved viral suppression 
to < 400 HIV-1 RNA copies/mL, as well as viral suppression to ‘Non Detectable’ or < 50 HIV-1 
RNA copies/mL after re-initiation of ART.  
The by-subject analysis of PhenoSense® Entry Assay data for PRO140, maraviroc, and 
AMD3100 shows no significant changes in the post-treatment IC50 and IC90 values were noted 
when compared with baseline values in virologic failure and non-virologic failure groups of 
subjects. As the aggregate analysis shows for initial 40 subjects, the subjects who experienced 
virologic failure had higher IC90 value for PR0140 at baseline compared to subjects without 
virologic failure. The mean IC90 for subjects who experienced virologic failure was higher (10.84 
µg/mL) than the IC90 for subjects without virologic failure (6.70 µg/mL) in the CD01 study 
(p=0.0115).  
Anti-PRO140 antibodies were not identified in any post-treatment sample and data derived from 
the CD01 study further supports the favorable PRO140 PK profile data generated from both pre-
clinical as well as prior Phase 1/2 clinical trials. 
Safety data were analyzed for all 43 enrolled subjects. One (1) of 43 subjects experienced an SAE 
that was deemed not related to the study drug by the Principal Investigator. Twenty-eight (28) of 
43 subjects (67%) experienced one or more adverse events (Aes) after receiving at least one dose 
of PRO140. The most commonly occurring Aes were infections and infestation conditions which 
were reported by 14 of 43 (32.5%) subjects. The majority of the reported Aes (62/87; 71.2%) 
were deemed either unlikely or not related to study treatment by the Investigator. Similarly, the 
majority of the reported Aes (70/87; 80.4%) were deemed mild in nature.  
1.4.11. PRO 140_CD01 Extension Study 
PRO 140_CD01-Extension study (open-label, 28 subjects, multi-center) seeks to evaluate the 
efficacy, safety, and tolerability of PRO 140 monotherapy (350 mg subcutaneous injection 
weekly) for the continued maintenance of viral suppression following substitution of antiretroviral 
therapy in HIV patients (with exclusive CCR5-tropic virus). Participants in this study were HIV-
infected individuals who were virologically suppressed on combination antiretroviral therapy and 
completed the first 12 weeks of CD01 study without experiencing virologic failure. As with the 
CD01 study, virologic failure was defined as two consecutive HIV-1 RNA levels of ≥ 400 
copies/mL separated by at least 3 days. Consenting patients may remain on PRO 140 
monotherapy until PRO 140 receives marketing approval or IND is withdrawn by Sponsor.  
A total of 17 subjects participated in the CD01-Extension study of which one subject was 
considered not eligible as subject experienced virologic failure prior to first extension treatment. 
Sixteen (16) eligible subjects (M/F: 14/2) with median age of 54.9 years (26-68) and median CD4 
T-cell count of 593 cells/mm3 (365-1059) were enrolled in an extension study. One patient 

 
 
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discontinued at week 37 (with viral load of <40 copies/mL) due to relocation. Two subjects were 
withdrawn due to non-treatment related SAEs at week 140 and 149, respectively. One subject was 
withdrawn due to re-starting their ART at week 99. Two subjects withdrew consent at week 81 
and 139, respectively. Five (5) subjects experienced virologic failure (VF) (two consecutive viral 
load of ≥400 copies/mL). The mean time to virologic failure was 329 days (106-691).  
Five (5) subjects are currently receiving weekly 350 mg PRO140 SC monotherapy and have 
completed more than three years of treatment (176 – 198 weeks). Overall, 12 subjects completed 
at least one year of treatment and 9 subjects completed at least two years of treatment in this study 
PRO140 was generally well tolerated, and no drug-related SAEs were observed.  
This clinical study is currently ongoing. 
1.4.12. PRO 140_CD02 Study 
PRO 140_CD02 study (double blind, placebo controlled, 52 subjects, multi-center) seeks to 
evaluate the efficacy, safety, and tolerability of PRO 140 in combination with either existing ART 
(failing regimen) or Optimized Background Therapy (OBT) in patients infected with HIV-1. The 
study population includes 52 adult patients with a documented history of genotypic or phenotypic 
resistance to ART drugs within two or more drug classes who demonstrate evidence of HIV-1 
replication despite ongoing antiretroviral therapy and have limited treatment options. The options 
may be limited as a result of drug antiviral class cross-resistance, documented treatment 
intolerance, documented objective assessments such as renal or hepatic insufficiency (e.g. high 
creatinine at baseline, limiting treatment options due to potential for toxicity), past adverse 
reactions such as hypersensitivity reactions or neuropsychiatric issues that could limit use of 
currently approved drugs. 
In Part 1 of double-blind treatment period, virally non-suppressed subjects will be randomized 
and treated with either PRO 140 or Placebo in combination with the failing ART regimen for 7 
days until HIV-1 genotypic drug resistance assay results are available to construct an OBT. The 
primary efficacy endpoint is proportion of participants with ≥ 0.5 log10 reduction in HIV-1 RNA 
viral load from baseline at the end of the 7 day functional monotherapy period. 
In Part 2 of double-blind treatment period, subjects will continue treatment with PRO 140 in 
combination with OBT within the 24-week open-label period.  
Fifty-two subjects with a mean age of 52.4 years, 73.1% male, 48.1% non-white and mean 
duration of HIV-1 infection of 20.4 years were randomized 1:1 to the PRO 140 SC or placebo 
arm. Subjects had been previously exposed to an average of 11 ART drugs and had documented 
resistance to >9 ART drugs. Mean baseline VL and CD4 cell count were 21,104 c/mL and 297.8 
c/mm3, respectively. The primary efficacy endpoint- the proportion of patients with ≥0.5 log10 

 
 
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reduction in HIV-1 VL from baseline at the end of the 1-week double-blind, randomized, 
placebo-controlled treatment period- was met (16/25 vs 6/26 [p-value <0.0032, ITT population]). 
Forty seven (47) of 52 patients have completed the 25-week study. Approximately 81% of 
patients completing 25-weeks of PRO 140 SC treatment demonstrated HIV-1 VL <50 c/mL and 
92% had HIV-1 VL <400 c/mL. Continued access to PRO 140 SC was provided through a 
rollover study and 40 patients entered the extension protocol after completing the CD02 study. 
PRO 140 SC was generally well tolerated. No drug-related SAEs or treatment discontinuations 
were reported in the study. 
This clinical study is completed pending final database lock.  
1.4.13. PRO 140_CD02 Extension Study 
PRO 140_CD02 Extension study (open label, 40 subjects, multi-center) seeks to evaluate the long 
term efficacy, safety and tolerability of PRO 140 weekly injection in combination with Optimized 
Background Therapy (OBT) in patients infected with HIV-1. The study population includes 40 
treatment-experienced HIV-infected adult patients with CCR5-tropic virus who successfully 
completed PRO 140_CD02 study and continue to demonstrate HIV-1 viral suppression. 
This clinical study is currently ongoing. 
1.4.14. PRO 140_CD03 HIV Study 
PRO 140_CD03 HIV (open-label, 350 subjects, multi-center) is a three part study enrolling 
virally suppressed HIV-1 patients with CCR5-tropic HIV-1 receiving combination antiretroviral 
(cART) therapy. Patients received weekly doses of PRO 140 on single-agent maintenance therapy 
following one week of overlap of the existing cART regimen that is then discontinued. In part 1, 
156 participants received 350 mg PRO 140 SC in a single-arm design. In part 2, 147 participants 
received 350 or 525 mg PRO 140 SC in a 1:1 ratio as randomized controlled, two-arm study. In 
an ongoing part 3, 51 participants have been randomized to receive 525 or 700 mg PRO 140 SC 
in a 1:1 ratio.  
Despite reaching the enrollment target of 350 subjects for the PRO140_CD03 HIV study, the 
enrollment is ongoing as the goal of enrolling 20 subjects for the CNS sub-study have not 
achieved. As a result, sites that are currently participating in the CNS sub-study are permitted to 
continue enrollment in the CD03 HIV study. 
Of the 354 patients enrolled, median age was 51 yrs (21-77) with the majority reported as male 
(79%) and 37% were non-white. A total of 27 subjects have been randomized to 700 mg dose. In 
addition, another 18 subjects have been exposed to 700 mg dose after rescuing from the lower 
doses (350 mg or 525mg). On average, participants were diagnosed with HIV-1 infection for 16.8 
yrs and were on cART regimen for 14.8 yrs. The frequency and severity of injection site reactions 

 
 
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were comparable between the three dose groups (350, 525 and 700mg) and the incidence or 
severity of injection site reactions was not increased in patients receiving higher doses. Overall, 
PRO 140 SC was generally well tolerated at all dose levels in this study. 
This clinical study is currently ongoing. 
1.4.15. PRO 140_CD03 HIV Extension Study 
PRO 140_CD03 study (open-label, 350 subjects, multi-center) seeks to evaluate the long term 
efficacy, safety and tolerability of PRO 140 SC as long-acting single-agent maintenance therapy 
in virologically suppressed subjects with CCR5-tropic HIV-1 infection. The study population 
includes up to 300 treatment-experienced HIV-infected adult patients who successfully completed 
PRO 140_CD03 HIV study and continue to demonstrate HIV-1 viral suppression. 
This clinical study is currently ongoing. 
1.4.16. PRO 140_CD06 Study 
PRO 140_CD06 study (double-blind, 80 subjects, single-center) seeks to evaluate the evaluate 
comparability of PRO 140 formulation Batch Lot # 3-FIN-3143 versus formulation Batch Lot# 3-
FIN-2618 as a one-time subcutaneous (SC) injection in healthy subjects under non-fasting 
conditions.  
1.4.17. PRO 140_CD07 Study 
CD07_TNBC study (open-label, two-part [Phase Ib: Up to 18 subjects; Phase II: 30 Subjects], 
multi-center) seeks to evaluate the efficacy, safety, tolerability and maximum tolerate dose 
(MTD) of leronlimab (PRO 140) when combined with carboplatin in patients with CCR5+ 
metastatic triple-negative breast cancer (mTNBC). 
The study population includes patients with CCR5-positive, locally advanced or metastatic triple-
negative breast cancer (mTNBC) who are naïve to chemotherapy in metastatic setting but have 
been exposed to anthracyclines and taxane in neoadjuvant and adjuvant settings (first-line). 
This clinical study is currently ongoing. 
1.4.18.  CD08_mCRC Study 
CD08_mCRC study (open-label, 30 subjects, multi-center) seeks to evaluate the effect on overall 
response rate (ORR) of Leronlimab (PRO 140) when combined with Regorafenib in patients with 
CCR5+, Microsatellite Stable (MSS), Metastatic Colorectal Cancer (mCRC).  
The study population includes patients with CCR5+, Microsatellite Stable (MSS), metastatic 
Colorectal Cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- 

 
 
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adequate endpoint in this population when evaluating the role of biological agents including 
PARP-inhibitors and antiangiogenic agents such as bevacizumab. 
Metastasis is the primary cause of death in patients with breast cancer. Currently no treatments 
exist that are directed specifically to the metastatic process. The current proposal provides strong 
preliminary evidence that: 1) a receptor, CCR5, is expressed in a subset of human breast cancer, 
2) CCR5 is intrinsically related to invasiveness and metastasis cascade, 3) CCR5 is associated 
with upregulation of PD-L1 and the adaptative immune system process of tumor evasion, 4) 
CCR5 correlates with DNA repair activities. Furthermore, CCR5 inhibitors, previously developed 
and FDA approved for treatment of HIV patients, can effectively block breast cancer metastasis in 
preclinical models. The repurposing of drugs for alternative use in cancer metastasis, drugs that 
were previously approved by the FDA, may provide a more rapid solution for this deadly disease.  
1.5.2. Rationale for Dose Selection 
Leronlimab (PRO 140) is currently under development for the indication of HIV in combination 
with other antiretroviral agents or as single agent maintenance therapy for the treatment of only 
CCR5-tropic human immunodeficiency virus type 1 (HIV-1) infection. The safety profile of 
leronlimab (PRO 140) has been extensively evaluated in clinical trials of HIV-positive patients. 
PRO 140 has been administered intravenously or subcutaneously to more than 750 healthy and 
HIV-1 infected individuals in Phase I/II/III studies. The drug has been well tolerated following 
intravenous administration of single (or multiple) doses of 0.5 to 10 mg/kg or up to 700 mg 
weekly doses as subcutaneous (SC) injection. Overall, 324 subjects have been exposed to PRO 
140 350 mg SC weekly dose with the longest duration of exposure lasting 4 years. Similarly, more 
than 250 and 150 subjects have been exposed to PRO 140 525 mg and 700 mg SC weekly dose, 
respectively. No dose-proportional increases in incidence and severity of AEs were reported at 
the 700 mg dose compared to the 525 mg and 350 mg dose levels of PRO 140 (leronlimab).  
We anticipate a manageable safety profile with combination therapy since: 1) Leronlimab (PRO 
140) is not metabolized by the liver, and therefore may have the potential for a better tolerability 
profile than many of the existing small-molecule therapies; 2) Unlike small molecules, 
monoclonal antibodies are too large to be filtered by the kidneys and are not eliminated in the 
urine, except in pathologic conditions. If low molecular weight antibody fragments are filtered, 
they are usually reabsorbed and metabolized in the proximal tubule of the nephron. These 
pharmacodynamic characteristics and current safety profile led to the selection of 350 mg of 
leronlimab (PRO 140) as the starting dose in combination with other chemotherapy agents. 
Once the maximum tolerated dose (MTD) has been established/reached under the ongoing dose-
escalation study of Leronlimab in combination with carboplatin in patients with Metastatic Triple-
Negative Breast Cancer (CD07 TNBC Study), the dose of Leronlimab given in combination with 
other chemotherapy agents will be modified accordingly for this CD07 TNBC Compassionate-
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Note: Based on successful safety data review for the first three subjects enrolled in CD07_TNBC 
Study in Cohort A (350 mg leronlimab SC weekly + AUC 5 Carboplatin every 3 weeks), dose 
escalation to proceed with enrollment of subjects under Cohort B (525 mg leronlimab SC weekly 
+ AUC 5 Carboplatin every 3 weeks). The similar dose change of Leronlimab in combination 
with other chemotherapy agents is now implemented under the current protocol version for the 
CD07 TNBC Compassionate-Use Study. 
1.6 
RISKS / BENEFITS ASSESSMENT 
1.6.1. Risks/Discomfort to Subjects and Precautions to Minimize Risk 
Allergic Reaction 
Leronlimab (PRO 140) belongs to the monoclonal antibody class of drugs. Monoclonal antibodies 
are sometimes associated with allergic reactions or flu-like reactions (such as fever, chills, and 
aches) or injection-site reactions. These events are usually of short duration if they occur at all. 
Severe allergic reactions, however, can be life-threatening. Although anaphylaxis has not been 
observed in prior trials of leronlimab (PRO 140), infusion of proteins always carries with it the 
theoretical risk for anaphylactic shock. Accordingly, whenever leronlimab (PRO 140) is 
administered to subjects, there should be available and in place the procedures required to manage 
anaphylactic shock. 
Immune Response 
People who take leronlimab (PRO 140) or other monoclonal antibodies can also develop an 
immune response to leronlimab (PRO 140) that may affect their ability to receive monoclonal 
antibodies, or to benefit from diagnosis or therapy with a monoclonal antibody in the future. 
Pregnancy 
Risks to unborn babies are unknown at this time; pregnant females will be excluded from this 
study. Females of childbearing potential must have a negative pregnancy test prior to enrollment. 
Both male and female patients and their partners of childbearing potential must agree to use 
appropriate birth control methods throughout the study duration (excluding women who are not of 
childbearing potential and men who have been sterilized).  
Venipuncture 
Blood sampling is required as part of the study protocol. Blood sampling carries a minimal risk of 
minor discomfort and the possibility of minor bruising at the site of the needle puncture and, 
rarely, the possibility of infection at the needle puncture site. 

 
 
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Core or excisional biopsy 
A core or excisional biopsy may be necessary in order to evaluate the CCR5 receptor status of the 
breast cancer tumor by Immunohistochemistry (IHC) assay. This assay will be performed in 
archival tissue from previous biopsy specimens. If archival tissue is not available then, fresh core 
or excisional biopsy will be done. Serious complications related to core biopsy are rare. The 
commonest problem is bleeding, which is usually easy to control at the time of the procedure. 
Rarer complications of core biopsy include infection and abscess formation, pneumothorax, milk 
fistula formation, cosmetic deformity and seeding of tumor along the biopsy track. Compared to a 
needle biopsy, a surgical biopsy is more invasive, has a longer, more uncomfortable recovery time 
and has a higher risk of infection and bruising. 
Unknown Risks 
As with all research there is the remote possibility of risks that are unknown or that cannot be 
foreseen based on current information.  
Theoretical risk for increased severity of West Nile virus infection 
Individuals who lack a functional CCR5 gene are at increased risk for severe infection by West 
Nile virus [Thompson, 2009]. Because of this, treatment with CCR5 co-receptor antagonists poses 
a theoretical risk for increased severity of West Nile virus infection. However, this concern is 
mitigated by several factors. First, no increased risk was observed for individuals who possess 
one functional and one non-functional CCR5 gene, indicating that an intermediate amount of 
CCR5 is sufficient for defense against West Nile virus [Thompson, 2009]. Second, use of CCR5 
co-receptor antagonists is unlikely to completely abrogate CCR5 function, and there has been no 
association reported to date between CCR5 co-receptor use and severe West Nile virus. 
Additionally, leronlimab (PRO 140) weakly antagonizes the natural activity of CCR5 and thus is 
less likely to adversely affect immune function. However, patients enrolled in this study may have 
immune suppression from chemotherapy and therefore, DSMB and the investigators will be 
alerted to risks of West Nile infections. Furthermore, this has not been established to be a risk 
with maraviroc, the other FDA-approved anti-CCR5 drug already. 
Collectively, the experience with both IV and SC, simulation modeling and the recent 
confirmation that a higher concentration of leronlimab (PRO 140) synthesized using a highly 
efficient CHO cell line can be conveniently and safely administered has resulted in the design of 
the current study.  
1.6.2. Intended Benefit for Subjects 
This study provides an opportunity for subjects with CCR5 + metastatic triple negative breast 
cancer previously treated in neoadjuvant and adjuvant settings to have once weekly SC treatment 

 
 
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with leronlimab (PRO 140) in combination with treatment of physician’s choice (TPC). Subjects 
participating in the present study will contribute to the development of a drug which has the 
potential to become a treatment option for them and others in the future. 
 

 
 
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2 STUDY OBJECTIVES 
Primary Objective: 
The primary objective of this study is to assess anti-tumor activity of Leronlimab (PRO 140) in 
combination with Treatment of Physician’s Choice in the treatment of patients with CCR5+ 
Metastatic Triple Negative Breast Cancer (mTNBC) as part of a defined treatment protocol. 
Secondary Objectives: 
The secondary objective of this study is to collect further safety, tolerability and efficacy data. 
To evaluate correlative studies for better treatment selection in future validation studies 

 
 
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This is a single arm, compassionate use study with 30 patients for leronlimab (PRO 140) 
combined with a treatment of physician’s choice (TPC) in patients with CCR5+ mTNBC.  
Leronlimab (PRO 140) will be administered subcutaneously as weekly dose of 525 mg until 
disease progression or intolerable toxicity. Treatment of Physician’s Choice (TPC) is defined as 
the following drugs administrated according to local practice: eribulin, gemcitabine, capecitabine, 
paclitaxel, nab-paclitaxel, carboplatin, or atezolizumab (or other checkpoint inhibitors). The 
selected treatment should be administered as per the dosing schedule included on the package 
insert.  
Patients will be evaluated for tumor response approximately every 3 months or according to 
institution’s standard practice by CT, PET/CT or MRI with contrast (per treating investigator’s 
discretion) using the same method as at baseline. Tumor measurements will be done using 
RECIST v1.1.  
Note: Subjects participating under Protocol version 1.0 – 3.0 received 350 mg of PRO 140. Dose 
was increased from 350 mg to 525 mg weekly under version 4.0 of this protocol.   
Subjects enrolled under previous versions of the protocol have the option of remaining on their 
current dose of 350mg or increasing their dose to 525 mg for the remainder of the trial. 
3.1 
STUDY CENTER 
Up to 10 centers in the United States (US). 
3.2 
STUDY POPULATION 
The target population for this study is subjects with histologically confirmed mTNBC that express 
CCR5 (> 10% membranous staining completed at the laboratory at the Medical College of 
Wisconsin). 
This will be a multicenter trial. A total of 30 subjects will be needed for this trial. 
Eligibility will be evaluated by the study team according to the following criteria. Eligibility 
waivers are not permitted. Subjects must meet all of the inclusion and none of the exclusion 
criteria to be registered to the study.  
3.3 
ELIGIBILITY CRITERIA 
3.3.1. Inclusion Criteria 
Subjects are required to meet all of the following criteria for enrollment into the study: 

 
 
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1. Must have a histologically confirmed diagnosis of TNBC. Must demonstrate HER-2 
negative (IHC 0, 1+, or fluorescence in situ hybridization (FISH) negative and ER< 1%, 
and PR < 1%, per ASCO/CAP criteria);  
Note: Patients with ER and/or PR <10% who have failed on endocrine therapy will also 
be eligible for participation in the study. 
2. Demonstrate CCR5 + by IHC (>10% of primary or metastatic tumor cells shows 
membranous staining and/or high predominance of CCR5+ tumor-infiltrating leukocytes 
completed at the reference laboratory of Dr. Hallgeir Rui at Medical College of 
Wisconsin).  
Note: This test will be done as part of the pre-screening period. It will be performed in 
archival metastatic tissue. If archival tissue is not available then, fresh biopsy will be 
done; 
3. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion (in case archival tissue is not available); 
4. Patients with de novo (metastatic or stage IV at initial diagnosis) breast cancer OR 
Patients with locally recurrent or metastatic breast cancer who have been treated up to 3 
previous line of systemic therapies (including neo/adjuvant setting) and had progressed or 
were intolerant to the latesttreatment. 
 
Note: Patients with PDL-1+ that elect not to receive checkpoint inhibitor or are excluded 
for medical conditions will be eligible for participation in the study.  
5. Patients must have measurable disease based on RECIST v1.1; 
6. Female patients, ≥ 18 years of age; 
7. Patients must exhibit a/an ECOG performance status of 0-1; 
8. Life expectancy of at least 6 months; 
9. Patients must have adequate organ and bone marrow function within 28 days prior to 
registration, as defined below: 
 leukocytes ≥ 3,000/mcL; 
 absolute neutrophil count ≥ 1,500/mcL; 
 platelets ≥ 100,000/mcL; 
 total bilirubin: within normal institutional limits; 
 AST(SGOT) &ALT(SPGT) ≤ 2.5 X institutional upper limit of normal (ULN) 
(applicable to all patients, irrespective of liver disease or metastasis); and 

 
 
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 creatinine: within normal institutional limits. 
10. Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not 
clinically significant by the Principal Investigator. 
11. Females of child-bearing potential (FOCBP) and males must agree to use two medically 
accepted methods of contraception with hormonal or barrier method of birth control, or 
abstinence, prior to study entry, for the duration of study participation and for 60 days 
after the last dose of study drug (Refer to Appendix 1). Should a female patient become 
pregnant or suspect she is pregnant while participating in this study, she should inform her 
treating physician immediately. NOTE: A FOCBP is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets 
the following criteria: 
 Has not undergone a hysterectomy or bilateral oophorectomy; and 
 Has had menses at any time in the preceding 12 consecutive months (and therefore 
has not been naturally postmenopausal for > 12 months). 
12. FOCBP must have a negative serum pregnancy test at Screening Visit and negative urine 
pregnancy test prior to receiving the first dose of study drug; and 
13. Patients must have the ability to understand and the willingness to sign a written informed 
consent prior to registration on study. 
3.3.2. Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from enrollment: 
1. HER-2 overexpressed/amplified MBC (Appendix 2 for guidelines from ASCO); 
2. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
28 days prior to enrollment; 
3. Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to leronlimab (PRO 140) are not eligible; 
4. Patients who have had prior exposure to CCR5 antagonists are not eligible; 
5. Patients who have a known additional malignancy that is progressing or requires active 
treatment are not eligible. Patients who have had a prior diagnosis of cancer and if it has 
been <3 years since their last treatment are not eligible. Exceptions include basal cell 
carcinoma of the skin or squamous cell carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical cancer; 

 
 
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6. Has an active infection requiring systemic therapy. Note: Patients must complete any 
treatment with antibiotics prior to registration; 
7. Patients who have a known HIV positive status or known/ active Hepatitis B and/or C 
infection are not eligible; 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Note: Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have returned 
to baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability; 
9. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator; 
10. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial; and 
11. Is pregnant or breastfeeding, or expecting to conceive or have children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
the duration of study participation. 
 

 
 
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4 STUDY SCHEDULE 
The total study duration for each subject consists of pre-screening, screening, treatment, and 
follow-up periods. A study flow diagram is presented in Figure 4-1Figure 4 1. 
 Pre-Screening Period: A separate Informed Consent Form (ICF) will be used for the pre-
screening. The pre-screening period is designed for evaluation of histologically confirmed 
diagnosis of mTNBC (documented by HER-2 negative, ER<1%, PR<1%) and CCR5 
positive status by Immunohistochemistry (IHC) assay. This assay will be performed in 
archival tissue from previous biopsy specimens. If archival tissue is not available then, 
fresh core or excisional biopsy will be done. If patient qualifies, then they will undergo 
full screening.  
 Screening Period: Screening assessments will commence after obtaining signed informed 
consent, and will include review of medical and medication history, demographic 
information and baseline disease characteristics, eligibility evaluation, physical 
examination, vital signs, height and weight, concomitant medications, electrocardiogram 
(ECG), tumor imaging assessment (prior imaging assessment within the last 3 months of 
the Screening Visit is acceptable), routine serum biochemical, hematologic, urinalysis, 
serum pregnancy (if applicable). These assessments must be conducted within 28 days of 
the first treatment visit. 
 Treatment Period: Subjects who meet the eligibility criteria will have completed 
following evaluations and assessments before receiving treatment: a) review of medical 
and medication history; b) physical examination, vital signs and documentation of ECOG 
performance status; c) ECG; d) routine serum biochemical, hematologic, urine pregnancy 
(if applicable) and urine laboratory assessments. Additionally, a blood sample will be 
collected prior to treatment administration for CTCs PD-L1/CCR5 and CTC - CAMLs 
analysis. 
 Leronlimab (PRO 140) will be administered subcutaneously weekly in combination with a 
treatment of physician’s choice. The study treatment will be administered by a licensed 
medical professional at clinic site or self-administered by subjects at home.  
 Note: All initial leronlimab (PRO 140) SC weekly injections must be administered at 
clinic. The remaining study treatment injections may be self-administered by subjects at 
home after proper training by a healthcare professional. 
 Subjects will be allowed to continue treatment until any one of the following occurs: 
progressive disease or unacceptable toxicity or withdrawal of consent. 
 Follow-Up Period: An End of Treatment (EOT) visit will be conducted 30 (± 3) days 
after the last treatment visit (i.e., after last dose of leronlimab (PRO 140). Additionally, 

 
 
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[5] Weight only 
[6] Symptom-directed physical examination at clinic visits  
[7] A 12-lead ECG will be repeated during the study only if clinically indicated and at the discretion of the treating physician. 
[8] Prior tumor imaging assessment within the last 3 months of the Screening Visit is acceptable. During the Treatment Phase, scans are to be done 
approximately every 3 months or according to institution’s standard practice by CT, PET/CT or MRI with contrast (per treating investigator’s 
discretion) using the same method as at baseline. Tumor measurements will be done using RECIST v1.1. To be assigned a status of PR or CR, 
changes in tumor measurements must be confirmed by repeat assessments that should be performed 4-8 weeks after the criteria for response are 
first met. In the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 4-8 weeks. 
[9] Hemoglobin, Hematocrit (HCT), Red Blood Cells (RBC), White Blood Cells (WBC) with total and differential count, absolute lymphocyte count, 
absolute neutrophil count (ANC) and platelets. 
[10] Serum Biochemistry will include:  
Hepatic function indicators: total bilirubin, direct bilirubin, alkaline phosphatase, aspartate aminotransferase (AST)/SGOT, alanine 
aminotransferase (ALT)/SGPT, albumin and total protein.  
Renal function indicators: blood urea nitrogen (BUN), creatinine 
Electrolytes: sodium, potassium, chloride, calcium and bicarbonate 
Other: glucose (random) 
[11] Urine samples will be tested for pH, appearance, color, specific gravity, turbidity, ketones, bilirubin, blood, glucose, protein, nitrites, urobilinogen, 
and leukocyte esterases. Microscopic exam includes bacteria, cast, crystals, epithelial cells, RBC and WBC. 
[12] Only performed on women of childbearing potential 
[13] Blood sample collection for CTCs PD-L1/CCR5 analysis to be taken prior to the treatment administration at T1 and every 3 weeks thereafter, and 
at the end of treatment (EOT). 
[14] Blood sample collection for CTC and CAMLs analysis to be taken prior to treatment administration at T1 and every 3 weeks thereafter, and at the 
end of treatment (EOT). 
[15] Archival breast tissue (primary or metastatic site) will be collected from all patients at the pre-screening period and analyzed for presence of 
CCR5. Note: If no archival tissue is available, fresh biopsy to be done of the primary or metastatic site. 
[16] Breast tissue (primary or metastatic site) collected to analyze for the presence of CCR5 will additionally be used for evaluating PD-L1 expression 
levels. The PD-L1 expression testing will be performed at the reference laboratory using the formalin-fixed, paraffin-embedded (FFPE) tissue 
block or slides. 
[17] Leronlimab (PRO 140) is administered as subcutaneous injection in the abdomen weekly. A total of 525 mg (175 mg/mL) is delivered as two 
injections of 1.5 mL each on opposite sides of the abdomen.  

 
 
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[18] Injection Site Reaction Assessment as assessed by Investigator (or designee) at the clinic visits. Injection Site Reaction Assessment will not be 
applicable if leronlimab (PRO 140) is self-administered by subjects at home. 
[19] Subject-perceived injection site pain (average pain since last treatment) will be assessed using the Pain Visual Analog Scale (VAS) prior to each 
study treatment administration which evaluates average pain since last treatment. Injection Site Pain Assessment will not be applicable if 
leronlimab (PRO 140) is self-administered by subjects at home. 
[20] Subjects will be followed up by clinic visits or phone call or another method of contact, for survival status every 3 months (±1 month) for 2 years 
after treatment discontinuation or until death, whichever occurs first 
[21] All subjects will be followed for adverse events for 30 days after last dose of leronlimab (PRO 140), or until the subject starts a new treatment, 
whichever occurs first. 
[22] Subjects who discontinue treatment for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event (i.e. the 
grade is not changing). If a subject stops treatment due to unacceptable adverse event(s) but has not demonstrated disease progression, then the 
subject will be followed with imaging studies every 9 weeks until the time of progression radiographically according to RECIST v1.1 criteria. In 
the event that a radiographic response is detected, then this event will be included as a response in the final analysis, and the time of progression 
used in calculation of the survival analysis. 
[23] Limited to all subsequent anti-cancer treatments. 
[24] Can be performed within 3 days prior to each treatment visit. 
[25] Subjects will receive treatment assigned by the physician on the regimen's established schedule. See Section 7.177.17 
[26] Subjects can continue to receive treatment until one of the following occurs: progressive disease, unacceptable toxicity, or withdrawal of consent 
[27] CBC, biochemistry, and urinalysis testing schedule (i.e., every 21 days) is allowed to be modified by the treating oncologist (or Investigator) based 
on standard of care chemotherapy regimen. Must be performed at least once every 28 days (4 weeks). 

 
 
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4.1 
PRE-SCREENING PERIOD 
4.1.1. Pre-Screening Visit 
Sites are required to pre-screen subjects for study inclusion, evaluating CCR5 positive status by 
Immunohistochemistry (IHC) assay prior to performing a full screening visit. This assay will be 
performed in archival tissue from previous biopsy specimens. If archival tissue is not available 
then, fresh core or excisional biopsy will be obtained. 
The subject will sign and date the pre-screening informed consent form (ICF) in-person or 
remotely prior to any study-related pre-screening procedures. The remote consenting will involve 
the site sending the pre-screening ICF to subject (via hard copy or email) to discuss the consent 
over the phone. The written informed consent must be signed and personally dated by the subject, 
sent back to the site and will then be signed by the person who conducted the informed consent 
discussion. The consent process and discussion over the phone will be captured in the medical 
records.  
A unique identification number will be assigned to each subject who has provided written pre-
screening informed consent. The subject unique identification number will incorporate a three-
digit Study Center number (751, 752 or 753….) and a three-digit numeric ID assigned in 
successive order of entering the study after signing the pre-screening ICF at each center, 
beginning with 001 at each site (e.g. 751-001 or 752-001).  
Subject Screening # : 
XXX
- 
YYY 
 
XXX=Study Center
 
YYY=Subject Numeric ID 
Once the pre-screening ICF has been signed, the following procedures and information will be 
obtained to confirm pre- eligibility including: 
 Review of prior medical records 
 CCR5+ status confirmed by archival or fresh biopsy from primary or metastatic site 
 Breast tissue sample collected (primary or metastatic) for PD-L1 expression level 
A pre-screening log will be maintained to capture the following information: 
 Subject unique identification number 
 Patient initials 
 Date pre-screened 
 Initial eligibility 

 
 
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 Date of re-consent (for the full consent form) or reason for ineligibility 
4.2 
SCREENING PERIOD 
4.2.1. Screening Visit (SV) 
The subject (or Legally Acceptable Representative (LAR)) will sign and date the informed 
consent form (ICF) and Health Insurance Portability Accountability Act (HIPAA) authorization 
(according to site policy and practices) prior to any study-related procedures. All study centers 
will be instructed to maintain the study-specific screening and enrollment logs at their sites. If a 
subject initially fails to meet inclusion/exclusion criteria and is later reconsidered for 
participation, the subject will be re-consented and assigned a new unique identification number at 
the time of re-screening. Subjects who fail their first screening attempt may be re-screened a 
maximum of once and may be enrolled if they are found to meet all inclusion and no exclusion 
criteria when re-screened. 
Once the Screening ICF has been signed, screening procedures and information will be obtained 
to confirm subject eligibility including: 
 Demographic information and baseline disease characteristics (see Section 7.37.3),  
 Medical history (see Section 7.47.4), 
 Prior medications assessment (see Section 7.57.5),  
 Vital Signs (see Section 7.67.6), 
 Body Weight & Height measurements (see Section 7.6), 
 Physical examination (see Section 7.77.7), 
 Eastern Cooperative Oncology Group (ECOG) Performance Review (see Section 7.87.8) 
 12-lead Electrocardiogram (see Section 7.97.9) 
 Tumor imaging assessment (see Section 7.157.15) 
Note: Prior imaging assessment within the last 3 months of the Screening Visit is 
acceptable 
 Collection of lab specimens (see Section 7.117.11) for 
o Complete blood count 
o Biochemistry 
o Serum pregnancy test, for female subjects of childbearing potential. 

 
 
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o Urine sample for urinalysis parameters 
All screening information will be fully documented in the subject’s medical records (i.e., source 
documents).  
 For consented subjects who do not meet eligibility criteria, a Screen Failure Case Report 
Form (CRF) will be completed. The Screen Failure CRF will contain the following 
details: the subject identification number, the date of ICF signature, demographic 
information (see Section 7.37.3), and the reason for screen failure. No additional 
information will be required for subjects who fail screening.  
 For consented subjects who meet eligibility criteria, all required screening information 
will be transcribed onto the appropriate page of the CRF. 
4.3 
TREATMENT PERIOD 
Subjects who meet all eligibility criteria, as per data gathered from Screening Period are to be 
treated. All subjects who fail to meet eligibility criteria will be considered screen failure and exit 
the study without further evaluation 
The maximum sample size for this study is 30 subjects that will be followed by treatment 
according to the schedule described above starting at Treatment Visit 1 (Week 1). 
Treatment may continue until one of the following criteria applies: 
 Disease progression, 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), or 
 Withdrawal of consent 
4.3.1. Treatment Period, T1 (Week 1) 
The following assessments will be performed at the first treatment visit of the treatment period: 
 Concomitant medications assessment (see Section 7.57.5),  
 Vital Signs and body weight measurement (see Section 7.67.6), 
 Physical examination, including evaluation of all body systems (see Section 7.77.7) 
 ECOG Performance Status (see Section 7.87.8) 
 12-lead Electrocardiogram (see Section 7.97.9) 
 Collection of lab specimens (see Section 7.117.11 ) for 

 
 
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o Complete blood count 
o Biochemistry 
o Urine pregnancy test, for female subjects of childbearing potential. 
o Urine sample for urinalysis parameters 
o CTCs PD-L1/CCR5 analysis 
o CTC and CAMLs analysis 
 Note: Complete blood count, biochemistry and urinalysis can be performed within 3 days 
prior to each visit. 
 Leronlimab (PRO 140) Administration (see Section 6.1.36.1.3) 
 Post Injection Site Evaluation (performed by Investigator) (see Section 7.137.13) 
 Toxicity assessment (see Section 7.107.10) and Review of Adverse Events (see Section 
99) 
 Treatment of Physician’s Choice (See Section 7.177.17) 
4.3.2. Treatment Period, T2 (Week 2) Onward 
The following assessments will be performed at during the remaining visits during the treatment 
period: 
 Concomitant medications assessment (see Section 7.57.5),  
 Vital Signs (see Section 7.67.6), 
 Body weight measurement on T4, T7, T10, and every 3 weeks after (see Section 7.67.6), 
 Physical examination, including evaluation of all body systems on T4, T7, T10, and every 
3 weeks after (see Section 7.77.7) 
 ECOG Performance Status on T4, T7, T10, and every 3 weeks after (see Section 7.87.8) 
 Collection of lab specimens (see Section 7.117.11 ) for 
o Complete blood count 
o Biochemistry 
o Urine pregnancy test, for female subjects of childbearing potential on T4, T7, T10, 
and every 3 weeks after. 
o Urine sample for urinalysis parameters 
o CTCs PD-L1/CCR5 analysis on T4, T7, T10, and every 3 weeks after 

 
 
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o CTC and CAMLs analysis on T4, T7, T10, and every 3 weeks after 
 Note: Complete blood count, biochemistry and urinalysis can be performed within 3 days 
prior to each visit. 
 Leronlimab (PRO 140) Administration (see Section 6.1.36.1.3) 
 Post Injection Site Evaluation (performed by Investigator) (see Section 7.137.13) 
 Toxicity assessment (see Section 7.107.10) and Review of Adverse Events (see Section 
99) 
 Treatment of Physician’s Choice (See Section 7.177.17) 
Subjects will be allowed to continue treatment until any one of the following occurs: progressive 
disease or unacceptable toxicity or withdrawal of consent. 
4.4 
FOLLOW-UP PERIOD 
Duration of Follow Up 
 
An End of Treatment (EOT) visit will be conducted 30 (± 3) days after the last treatment visit 
(i.e., after last dose of leronlimab (PRO 140)). 
 
All patients will be followed for adverse events for 30 days after last dose of leronlimab 
(PRO 140) or until the patient starts a new treatment, whichever occurs first. 
 
Subjects who discontinue treatment for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event (i.e. the grade is not changing). 
 
If a subject stops treatment due to unacceptable adverse event(s) but has not demonstrated 
disease progression, then the subject will be followed with imaging studies every 9 weeks 
until the time of progression radiographically according to RECIST v1.1 criteria. In the event 
that a radiographic response is detected, then this event will be included as a response in the 
final analysis, and the time of progression used in calculation of the survival analysis. 
 
Subjects will be followed up by clinic visits or phone call or another method of contact, for 
survival status every 3 months (±1 month) for 2 years after treatment discontinuation or until 
death, whichever occurs first. 
4.4.1. End of Treatment Visit (EOT) 
An EOT visit will take place 30 (± 3) days from the last treatment visit.  
The following assessments will be performed at the EOT visit: 
 Concomitant medications assessment (see Section 7.57.5),  

 
 
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 Review of Adverse Events (see Section 99) 
 Vital Signs (see Section 7.67.6), 
 Physical examination, including evaluation of all body systems (see Section 7.77.7), 
 ECOG Performance Status (see Section 7.87.8), 
 12-lead Electrocardiogram (see Section 7.97.9), 
 Toxicity Assessment (see Section 7.107.10), 
 Collection of lab specimens (see Section 7.117.11) for 
o Complete blood count 
o Biochemistry 
o Urine sample for urinalysis parameters 
o CTCs PD-L1/CCR5 Analysis 
o CTC and CAMLs Analysis 
 Survival status (see Section 7.167.16) 
4.4.2. Survival Follow-up Visits 
Survival follow-up visits will be performed every 3 months (±1 month) for 2 years after treatment 
discontinuation or until death, whichever occurs first. Subjects will be followed up by clinic visits 
or phone call or another method of contact, for survival status. During the visit, the following 
assessments will be performed: 
 Survival status 
 Concomitant medications (limited to all subsequent anti-cancer treatments) 
 Toxicity assessment 
Note: Subjects who discontinue treatment for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event (i.e. the grade is not 
changing). 
 Tumor imaging assessment (see Section 7.157.15 and note below)  
Note: If a subject stops treatment due to unacceptable adverse event(s) but has not 
demonstrated disease progression, then the subject will be followed with imaging studies 
every 9 weeks until the time of progression radiographically according to RECIST v1.1 
criteria. In the event that a radiographic response is detected, then this event will be 
included as a response in the final analysis, and the time of progression used in 

 
 
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calculation of the survival analysis. 
4.5 
UNSCHEDULED VISITS 
In the event that the subject will return to clinic at a time other than a regularly scheduled study 
visit, the visit will be regarded as an unscheduled visit. Assessments at unscheduled visits are at 
the discretion of the Investigator. All pertinent findings, including adverse events or changes in 
medications, will be noted in the eCRF.  
Any hospitalization or ER visits in between the scheduled visits should be promptly notified to 
the site staff.  

 
 
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5 SUBJECT COMPLETION, WITHDRAWAL AND CRITERIA FOR 
STOPPING THE STUDY 
A subject is considered to have completed the study once all survival follow-up visit assessments up 
to 2 years after treatment discontinuation have been performed or until death, whichever occurs 
first.  
While subjects are encouraged to complete all study evaluations, they may withdraw from the study 
at any time and for any reason. Reasonable effort will be made to determine why any subject 
withdraws from the study prematurely. This information will be recorded. If a subject withdraws 
prematurely after dosing, subjects will be monitored until they are stable for discharge from the 
clinic. All data normally collected at the scheduled Post-Study (Follow-up) Visit should be recorded 
at the time of premature discontinuation. 
5.1 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT AND/OR STUDY AS A WHOLE 
Subjects can be taken off the study treatment and/or study as a whole at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation must be clearly documented on the 
appropriate eCRF and may include: 
 Subject voluntarily withdraws from treatment (follow-up permitted) 
 Subject withdraws consent (no follow-up permitted) 
 Subject is unable to comply with protocol requirements 
 Subject demonstrates disease progression 
 Subject experiences unacceptable toxicity 
 Treating physician determines that continuation on the study would not be in the subject’s 
best interest 
 Subject becomes pregnant 
 Subject develops a second malignancy that requires treatment which would interfere with 
this study 
 Subject becomes lost to follow-up (LTF) 
If a subject fails to return for the scheduled study visit or is discontinued from the study, an 
attempt will be made to determine the reason(s). If the subject is unreachable by telephone, a 
registered letter will be sent to the subject requesting that he/she contact the clinic.  

 
 
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All patients with an ongoing SAE at the Post-Study (Follow-up) Visit (scheduled or premature) 
must be followed until the event is resolved (with or without sequelae) or deemed stable. 
5.2 
DATA COLLECTED FROM WITHDRAWN SUBJECTS 
Every attempt should be made to collect follow-up information. The reason for withdrawal from 
the study will be recorded in the source documents and on the appropriate page of the CRF. 
Before a subject is identified as lost-to-follow up, the site should make all reasonable efforts to 
contact the subject. These attempts must be documented and should include at a minimum one 
phone call and one certified letter.  
In the event that a subject is withdrawn from the study at any time due to an adverse event or 
SAE, the procedures stated in Sections 9.29.2 and 9.49.4 must be followed. 
5.3 
SCREEN FAILURES 
A subject who signed a consent form, but did not meet the inclusion/exclusion criteria is 
classified as a screen failure. Subject number, demographics and reason for screen failure will be 
recorded. 
In the event that a subject initially fails to meet inclusion/exclusion criteria and is later 
reconsidered for participation, will be re-consented and assigned a new screening number at the 
time of re-screening. Subjects who fail their first screening attempt may be re-screened again (i.e., 
up to two screenings) and may be enrolled if they are found to meet all inclusion and no exclusion 
criteria at the subsequent screening visit. 

 
 
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6.1.1. Leronlimab (PRO 140) - Packaging and Labeling 
Study drug will be prepared by Ajinomoto Althea, Inc. and will be packaged, labeled, and shipped 
by PCI Pharma Services. 
The contents of each vial are described in Section 6.16.1. Leronlimab (PRO 140) kits will be 
labeled with information such as: study protocol #; fill volume; concentration; storage condition; 
a “use as per study protocol” statement; a cautionary statement; sponsor’s name and address; and 
the kit number. 
Below are representative samples of the Investigational Product, FDP individual vial (Figure 
6-1Figure 6-1), syringe label (Figure 6-2Figure 6-2), and kit labels (Figure 6-3Figure 6-3) 
designated for use in this clinical protocol. Each kit contains two labeled vials and two syringe 
labels.  
 
Figure 6-1: 
Investigational Product - Vial Label 
Protocol: PRO 140_CD07_Compassionate Use      Kit No. xx 
Subject No. _________        
Single use 3 mL vial contains 1.4 mL of PRO 140 (175 
mg/mL) solution for subcutaneous injection 
Store at 2oC to 8oC (36oF to 46oF) 
USE AS PER STUDY PROTOCOL 
Caution: New Drug – Limited by Federal (or United States) 
Law to Investigational Use 
CytoDyn Inc., Vancouver, WA, USA 
Protocol: PRO 140_CD07_Compassionate Use      Kit No. xx 
Subject No. _________        
Single use 3 mL vial contains 1.4 mL of PRO 140 (175 
mg/mL) solution for subcutaneous injection 
Store at 2oC to 8oC (36oF to 46oF) 
USE AS PER STUDY PROTOCOL 
Caution: New Drug – Limited by Federal (or United States) 
Law to Investigational Use 
CytoDyn Inc., Vancouver, WA, USA 
 
Figure 6-2: 
Investigational Product - Syringe Label 
Protocol: PRO 140_CD07_Compassionate Use                 Contents of Kit No. xxx 
This syringe contains 1.5 mL PRO 140 (175 mg/mL) solution for subcutaneous 
injection 
USE AS PER STUDY PROTOCOL 
Caution: New Drug – Limited by Federal (or United States) Law to 
Investigational Use 
CytoDyn Inc., Vancouver, WA, USA 
 

 
 
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Figure 6-3: 
Investigational Product - Kit Label 
Protocol: PRO 140_CD07_Compassionate Use                             Kit No. xxx 
Site No. ____________              Subject No. ________________   
This kit contains XX single-use vials 
Each 3 mL vial contains 1.4 mL of PRO 140 (175 mg/mL) solution for 
subcutaneous injection 
Store at 2oC to 8oC (36oF to 46oF) 
USE AS PER STUDY PROTOCOL 
Caution: New Drug – Limited by Federal (or United States) Law to Investigational 
Use 
CytoDyn Inc., Vancouver, WA, USA 
 
The pharmacy manual provides the criteria regarding vial acceptance or rejection, as well as 
instructions for the preparation of the IP syringes to be used to administer drug.  
6.1.2. Leronlimab (PRO 140) - Storage and Handling 
Study drug will be shipped at 2°C to 8°C (refrigerated [36°F to 46°F]) to the investigator’s site. 
Upon receipt at the site, the responsible site staff or pharmacist should verify the integrity of the 
vials. Study drug should be stored at 2°C to 8°C (refrigerated [36°F to 46°F]). The contents of the 
vial should appear as a clear to opalescent, colorless to yellow solution; fine translucent particles 
may be present. This is normal.  
The investigator must maintain an accurate record of the shipment, storage, and dispensing of the 
study drug in a drug accountability log. An accurate record including the date and amount of 
study drug dispensed to each subject must be available for inspection at any time. A study CRA 
assigned to monitor the investigational site will review these documents once study drug has been 
received by the investigational site. Study drug will be accounted for on an ongoing basis during 
the study. 
6.1.3. Leronlimab (PRO 140) - Administration 
Guidelines for dose preparation can be found in the pharmacy manual. 

 
 
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Leronlimab (PRO 140) will be provided to the administering personnel in single-use syringes 
prepared from vials of study drug stored at 2-8°C at the site pharmacy prior to use. Each of two 
syringes is filled to deliver 1 mL of study drug (per assigned dose).  
Equivalent volumes of leronlimab (PRO 140) will be administered subcutaneously on opposite 
sides of the abdomen.  
A 20-guage needle should be used to remove leronlimab (PRO 140) from vial and a 25-guage 
needle is used for administration to subjects. 
IP should be administered slowly over 15 seconds per mL. Leronlimab (PRO 140) should not be 
kept in syringe for longer than 60 minutes. 
Following each SC delivery of drug, careful examination will be made to assess the appearance of 
any study drug Injection Site Reactions (ISRs) as per CTCAE v5.0 
 All doses of study drug will be prepared by either the credentialed pharmacist or qualified 
medical professional and will be administered as SC injection by a licensed medical 
professional when leronlimab (PRO 140) is administered at clinic site. Self administration 
by subjects at home is allowed at certain visits. 
 All initial leronlimab (PRO 140) SC weekly injections a must be administered at clinic. 
The remaining study treatment injections may be self-administered by subjects at home 
after proper training by a healthcare professional. 
Note: It is preferred that the same injection site be used throughout the study. At the same time, it 
is not recommended to inject the study drug into areas where skin shows signs of a previous 
injection site reaction. It is advised to change the injection site if any previous injection site 
reaction remains unresolved. 
6.1.4. Leronlimab (PRO 140) - Post Injection Monitoring 
Subject will be observed at approximately 30 minutes post-injection or longer if necessary for 
injection site reaction as per CTCAE v5.0. 
In addition, the tolerability of repeated subcutaneous administration of leronlimab (PRO 140) is 
evaluated based on assessment of subject-perceived injection site pain using the Pain Visual 
Analog Scale (VAS).  
6.1.5. Leronlimab (PRO 140) - Dose Modifications 
The dose interruption and permanent discontinuation for any toxicity are described below. 
Dose interruption: Refer to Table 6-3Table 6 3 below. Recovery to acceptable levels must occur 
to allow leronlimab (PRO 140) continuation. Any adverse event deemed to be related to 

 
 
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6.1.8. Return and Retention of Study Drug 
All unused investigational products will be disposed of according to the investigational site policy 
for standard of care drugs. 
 
 
 

 
 
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7 DESCRIPTION OF PROTOCOL ASSESSMENTS AND PROCEDURES 
7.1 
INFORMED CONSENT 
A written informed consent will be obtained for this study for pre-screening and screening by the 
Investigator or designee from all subjects prior to performance of any protocol-specific procedure. 
This study will be conducted in accordance with the provisions of the Declaration of Helsinki.  
The Investigator must comply with applicable regulatory requirements and must adhere to the 
Good Clinical Practice (GCP) in the process of obtaining and documenting the informed consent. 
The Investigator, or designee, must also inform subjects of all pertinent aspects of the study. 
Before written informed consent is obtained from the subject, the Investigator or a person 
designated by the Investigator, must provide the subject enough time and opportunity to inquire 
about the details of the study and to decide whether or not to participate in the trial. All questions 
addressed by the subject about the study must be answered to the satisfaction of the subject. Prior 
to the subject’s participation in the trial, the written informed consent must be signed and 
personally dated by the subject and by the person who conducted the informed consent 
discussion. Authorization for release of protected health information must also be obtained, as per 
local policies.  
7.2 
ASSESSMENT OF ELIGIBILITY 
The Investigator must assess subject’ continued eligibility for the study as per the Inclusion and 
Exclusion criteria, during the Screening Period. The eligibility criteria are described in Section 
3.3.13.3.1 (Inclusion Criteria) and Section 3.3.23.3.2 (Exclusion Criteria). In the event that the 
subject is not suitable or eligible for the study, the subject will be considered “screen failure”.  
7.2.1. Re-screening 
If a subject fails initially to meet the eligibility criteria, and is later reconsidered for participation, 
the subject will be re-consented and assigned a new screening number at the time of re-screening. 
Subjects who fail their first screening attempt may be re-screened a maximum of once and may be 
enrolled in the study only if they meet all Inclusion and no Exclusion criteria when re-screened. 
7.3 
DEMOGRAPHIC INFORMATION AND BASELINE DISEASE CHARACTERISTICS 
In this study the demographic information will include: 
 Dates of ICF signature  
 Date of birth 
 Gender 

 
 
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 Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Pacific Islander, Caucasian, or other) 
 Ethnicity (Hispanic/Latino or Not Hispanic/Latino) 
In addition, the following baseline disease characteristics will be collected: 
 Year of initial diagnosis, 
 Tumor morphology (Ductal/NOS, Lobular, Medullary, Tubular, Other, or Unknown),  
 Histologic grade (I, II, III, or Unknown), 
 BRCA 1/2 status, 
 Menstrual status, 
 Location of metastasis (Brain, Visceral, Nonvisceral) 
7.4 
MEDICAL HISTORY 
A complete review of the subject’s past medical history (including all prior anti-tumoral therapy 
related to breast cancer), past surgeries, and current therapies (medications and non-medications) 
will be undertaken by the Investigator to check that all inclusion and no exclusion criteria have 
been met. 
Events that emerge prior to the first treatment (C1D1) will be recorded in the medical history and 
not as AEs. Aside from being used to determine subject eligibility, this information will permit 
the Investigator to record the nature, duration and severity of any ongoing baseline medical 
conditions prior to the subject’s receiving investigational product treatment.  
Medical histories will be recorded using the body system categories outlined below: 
 Cardiovascular 
 Lymphatic 
 Respiratory 
 Hematologic 
 Gastrointestinal 
 Immunologic 
 Renal 
 Dermatologic 
 Hepatic 
 Psychiatric 
 Neurological 
 Genitourinary 
 Endocrine 
 Other 
 
For each relevant history, the following will be documented:  
 Disease/disorder/condition 

 
 
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 Date of diagnosis 
 History status (resolved or ongoing). 
7.5 
CONCOMITANT MEDICATION 
The subject may be applied any medications judged necessary by the Investigator, provided such 
medications are not listed in Section 7.5.27.5.2.  
All concomitant medication administered or taken by the subject beginning 30 days prior to 
Screening Visit and throughout the study will be recorded in the source documents and on the 
appropriate page of the Case Report Form (CRF) including all prescription, over-the-counter 
(OTC), herbal supplements, and IV medications and fluids. If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be included on the 
CRF. 
Subjects must be questioned at each study visit concerning any new medications or changes in 
current medications including over-the-counter medication and topical medication. 
For each medication and non-study treatment, the following will be documented: 
 Medication/treatment name (generic name may be used if trade name is unknown) 
 Dose, unit, and frequency of dosing (individual dosages, not total daily dose).  
 Note: Each new dose of medication should be recorded as a separate entry, with the 
exception of medications that are given on a sliding scale. For these, it is acceptable to 
enter the range of the dosage, including the start and stop dates for which the specified 
dosage range was used. 
 Route of dosing 
 Indication for use 
 The start date  
 The stop date (if medication/therapy is not ongoing).  
 
7.5.1. Permitted Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.   
 

 
 
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7.5.2. Prohibited Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Period of this trial: 
 Anti-cancer systemic chemotherapy or biological therapy other than Treatment of Physician’s 
Choice (TPC) 
 Investigational agents other than leronlimab (PRO 140) 
 Radiation therapy 
7.6 
VITAL SIGNS, HEIGHT AND WEIGHT 
The following will be collected:  
 Vital signs: 
o Seated blood pressure (taken after the subject has been seated for at least 5 
minutes) 
o Pulse 
o Temperature (oral or tympanic) 
o Respiratory Rate 
 Height (at Screening Visit only) and Weight  
 BMI (derived from the height and weight measurements). 
7.7 
PHYSICAL EXAMINATION 
The physical examination will include routine examinations for the following: 
 Head, Ears, Eyes, Nose, Throat (HEENT) 
 Abnormalities of the extremities 
 Neurologic abnormalities 
 Heart/cardiovascular abnormalities 
 Musculoskeletal abnormalities 
 Dermatologic abnormalities 
 Any other body system for which an abnormality is noted and which, in the opinion of the 
Investigator, is relevant to the safety of the subject or could impact safety or efficacy 
results for the subject; i.e., the abnormality is clinically significant.  

 
 
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7.10 TOXICITY ASSESSMENT 
Any subject who receives at least one dose of study therapy will be evaluable for toxicity 
endpoints. Each subject will be assessed for the development of toxicity according to the 
timeframe referenced in the Schedule of Events table. Toxicity will be assessed according to 
CTCAE v 5.0 criteria. Also refer to Table 6-3Table 6 3 for the dose modification and 
management of leronlimab (PRO 140) for any toxicity.  
All subjects will be followed for adverse events for 30 days after last dose of leronlimab (PRO 
140), or until the subject starts a new treatment, whichever occurs first. 
Subjects who discontinue treatment for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event (i.e. the grade is not changing). If a subject stops 
treatment due to unacceptable adverse event(s) but has not demonstrated disease progression, then 
the subject will be followed with imaging studies every 9 weeks until the time of progression 
radiographically according to RECIST v1.1 criteria.  
7.11 CLINICAL LABORATORY ASSESSMENTS 
Blood samples will be collected for analysis of the following parameters: 
 Biochemistry and Complete Blood Count (CBC) Parameters: At Screening, T1 and every 
3 weeks thereafter, and at the end of treatment (EOT). 
 Serum pregnancy test (for female subjects of childbearing potential): At Screening 
 Urine pregnancy test (for female subjects of childbearing potential): T1 and every 3 weeks 
thereafter 
 CTCs PD-L1/CCR5 Analysis: T1 and every 3 weeks thereafter and at the end of treatment 
(EOT). 
 CTC and CAMLs Analysis: T1 and every 3 weeks thereafter and at the end of treatment 
(EOT). 
All laboratory reports will be reviewed by the Investigator. Abnormal results that are considered 
by the Investigator to be clinically significant, will be recorded as adverse events. If in the 
Investigator’s judgment, in order to make the determination of clinical significance the testing 
may be needed to be repeated. Validated, quality-controlled laboratory data will be transferred to 
the main database for analyses. 
 
 

 
 
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For CTC testing 
 
 
 
 
 
7.11.1.3 Assay Methodology 
CTCs Enumeration and PD-L1 
CTC isolation and enumeration will be performed using the US Food and Drug Administration-
approved CellSearch™ technology (Janssen Diagnostics). This technology consists of a semi-
automated system for the preparation of a sample [Al-Kateb, 2015] and is used with the 
CellSearch™ Epithelial Cell Kit. The procedure enriches the sample for cells expressing the 
epithelial-cell adhesion molecule with antibody- coated magnetic beads, and labels the cells with 
the fluorescent nucleic acid dye 4,2-diamidino-2- phenylindole dihydrochloride (DAPI). 
Fluorescently labeled monoclonal antibodies specific for leukocytes (CD45-allophycocyan) and 
epithelial cells (cytokeratin 8, 18, 19-phycoerythrin) are used to distinguish epithelial cells from 
leukocytes. A PD-L1 expression kit has been developed and is currently tested in clinical trial 
evaluating PD-L1 or PD-1 therapeutic targeting antibodies. 
CTCs and CAMLs using CellSieve™ 
The CellSieveTM microfiltration assay isolates circulating tumor cells (CTCs) and circulating 
cancer-associated macrophage-like cells (CAMLs) by size exclusion, identifying CTCs and 
CAMLs by their morphological features and the phenotypic expression of CCR5, cytokeratins 8, 
18, and 19, CD45 and DAPI.  Peripheral blood (7.5 mL) collected in CellSave preservative tubes 
is prefixed for 15 min, placed into the 30-mL syringe, and drawn through the filter in ∼3 min.  
The filtration instrument utilizes negative pressure to draw the sample through the filters at a 
gentle continuous rate.  The filter is then washed, postfixed, and permeabilized for 15 min. The 
filter and cells are stained with an antibody mixture and blocking buffer of FITC-conjugated anti-
cytokeratin 8, 18, 19, phycoerythrin (PE)-conjugated CCR5, and Cyanine5-conjugated CD45 
(Creatv MicroTech, Inc.).  
CTCs are CD45 negative cells with a pleomorphic nucleus and a filamentous cytokeratin positive 
phenotype.  CAMLs are large (21–300 μm in length) and morphologically distinct from CTCs.  
CAMLs are identified as single cells with an enlarged nuclear profile (14–64 μm in diameter) or 
separated polymorphic nuclei contained within the cell.  In addition, the nuclei are surrounded by 
a larger CD45 signal.  CAMLs can be identified further by vacuoles containing DAPI+ and/or 
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7.12 STUDY TREATMENT APPLICATION 
Refer to Section 6.16.1 for details. 
7.13 POST-INJECTION EVALUATION AND INJECTION SITE REACTION ASSESSMENT 
 At each treatment visit, an injection site reaction assessment will be made for the current 
and previous injection sites. Injection site reaction assessments are recorded by the 
Investigator starting after the first injection is given. Subject will be observed at 
approximately 30 minutes post-injection or longer if necessary for injection site reaction 
as per CTCAE v5.0. Refer to Sections 9.2.69.2.6 for more details. 
7.14 PAIN ASSESSMENT USING VISUAL ANALOG SCALE (VAS) 
Tolerability of repeated subcutaneous administration of leronlimab (PRO 140) is evaluated based 
on assessment of subject-perceived injection site pain using the Pain Visual Analog Scale (VAS). 
This assessment will be performed each time subjects arrive to the clinic for the study treatment 
visit. 
Before and immediately after each study treatment administration, subjects will be asked to mark 
the point that best represents the pain intensity over the past week at the time of injection 
administration on a horizontal line (100 mm in length) anchored by the following word 
descriptors at each end, “no pain" on the left side and "pain as bad as it could possibly be" on the 
right side of the line. The subject marks on the line or by pointing to a position on the line the 
point that they feel represents their perception of their pain state. The VAS score is determined by 
measuring in millimeters from the left-hand end of the line to the point that the patient marks. 
 
Figure 7-1: 
Visual Analog Scale 
 
 
7.15 TUMOR IMAGING AND RESPONSE EVALUATION 
For the purposes of this study, patients should be re-evaluated for tumor response approximately 
every 3 months or according to institution’s standard practice. In addition to a baseline scan, 

 
 
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confirmatory scans should also be obtained 4-8 weeks following initial documentation of 
objective response greater than Stable Disease (SD). 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
High resolution CT with oral/intravenous contrast or contrast-enhanced MRI is the preferred 
imaging modalities for assessing radiographic tumor response. If a subject has a known allergy to 
contrast material, please use local prophylaxis standards to obtain the assessment with contrast if 
at all possible, or use the alternate modality. In cases where contrast is strictly contraindicated, a 
non-contrast scan will suffice. Screening assessments should be performed within 28 days of 
registration. Brain MRI is the preferred imaging method for evaluating CNS metastasis, and 
assessment is required during screening in all eligible subjects. All known or suspected sites of 
disease (including CNS if history of CNS metastases) should be assessed at screening and at 
subsequent assessments using the same imaging method and technique. If more than one method 
is used at screening, then the most accurate method according to RECIST v1.1 should be used 
when recording data, and should again be used for all subsequent assessments. Previously treated 
CNS metastases are not considered measurable lesions for purposes of RECIST determined 
response. Subjects with a history of brain metastasis should have surveillance MRI approximately 
every 12 weeks, or sooner if clinically indicated. 
Radiographic tumor assessments will be conducted approximately every 3 months or according to 
institution’s standard practice by CT or MRI (per treating investigator’s discretion); the same 
modality used at baseline should be used throughout. Tumor measurements will be done using 
RECIST v1.1. Tumor assessments for all subjects should continue as per protocol even if dosing 
is interrupted. Tumor measurements should be made by the same investigator or radiologist for 
each assessment whenever possible. Changes in tumor measurements and tumor responses to 
guide ongoing study treatment decisions will be assessed by the investigator using RECIST. 
7.15.1. Definition of Lesions 
Tumor response will be assessed according to the RECIST (version 1.1; Eisenhauer et al. 2009). 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with 

 
 
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CT scan, MRI, or calipers by clinical exam (such measurements must be clearly documented). All 
tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  
To be considered pathologically enlarged and measurable, a lymph node must be ≥15mm in short 
axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 
mm). At baseline and in follow-up, only the short axis will be measured and followed. 
Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10mm or 
pathological lymph nodes with ≥10 to <15mm short axis) as well as truly non-measurable lesions. 
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
 Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 

 
 
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noncystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
7.15.2. Method of Assessment 
The same method of assessment and the same technique have to be used to characterize each 
identified and reported lesion at screening, at end of treatment and during follow-up. 
Clinically detected lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes). 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI should be performed with contiguous cuts of 5 mm or less in slice 
thickness, if possible [minimum measurable lesion size: long axis ≥ 10 mm (CT + MRI) and 2 x 
slice thickness, if the slice thickness is > 5 mm]. 
Ultrasound may only be used as a possible alternative to clinical measurements for superficial 
palpable lymph nodes, subcutaneous lesions, and thyroid nodules. 
7.15.3. Baseline documentation of ‘target’ and ‘non-target’ lesions 
Only subjects with measurable disease at baseline should be enrolled in this study. For evaluation 
of tumor response, lesions present at screening will be separated into target and non-target lesions 
according to the following criteria: 
Target Lesions: 
 All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  
 Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. 

 
 
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7.15.6. Evaluation of Best Overall Response 
The best overall response is the best response recorded from start of treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the start of treatment). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. Responses will be assessed using CT 
scans or magnetic resonance imaging according to standard RECIST v1.1 criteria in order to 
assess disease progression. These criteria will also allow for patients who experience an initial 
disease flare, and as some patients who will have a delayed response may experience an initial 
disease flare, these patients will be allowed to continue receiving study treatment beyond 
progression. 
The following table provides overall responses for all possible combinations of tumor responses 
in target and non-target lesions with or without the appearance of new lesions: 
 
Table 7-5: 
Time point response: subjects with target (± non-target) disease 
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 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = inevaluable. 
Note: To be assigned a status of PR or CR, changes in tumor measurements must be 

 
 
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Target lesions
Non-target lesions 
New lesions 
Overall response 
confirmed by repeat assessments that should be performed 4-8 weeks after the criteria 
for response are first met. In the case of SD, measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 4-8 weeks. 
7.15.7. Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met category 
when no lesions can be measured is not advised for CR until the first date that progressive disease 
is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
7.16 SURVIVAL STATUS 
Subjects will be followed up by clinic visits or phone call or another method of contact, for 
survival status every 3 months (±1 month) for 2 years after treatment discontinuation or until 
death, whichever occurs first.  
7.17 TREATMENT OF PHYSICIAN’S CHOICE 
Treatment of Physician’s Choice (TPC) is defined as the following drugs administrated according 
to local practice: 
 Eribulin  
 Gemcitabine  
 Capecitabine 
 Paclitaxel 
 Nab-paclitaxel 
 Carboplatin 
 Atezolizumab (or other checkpoint inhibitors) 

 
 
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The selected treatment should be administered as per the dosing schedule included on the package 
insert.  
 
 

 
 
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8 STATISTICAL ANALYSIS  
This section presents general information about statistical considerations and concepts and a brief 
discussion on analysis methodology, as well as some data conventions. Detailed descriptions of 
the statistical analysis methods and data conventions that will be used in this study will be in a 
separate document; i.e., the Statistical Analysis Plan (SAP). 
8.1 
TREATMENT GROUPS 
 525 mg leronlimab (PRO 140)  

 
 
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8.2 
SAMPLE SIZE DETERMINATION AND RATIONALE 
Up to 30 subjects will be enrolled in this study. The sample size for is based on clinical judgment. 
No statistical power calculation is used to establish the sample size. 
8.3 
RANDOMIZATION AND STRATIFICATION 
Not applicable. 
8.4 
BLINDING 
Not applicable.  
8.5 
INTERIM ANALYSIS 
No Interim Analysis (IA) will be performed for efficacy. 
8.6 
STATISTICAL CONSIDERATIONS 
All collected study data will be presented in subject data listings. Statistical analyses will be 
performed using SAS® for Windows, version 9.3 or later. Descriptive statistics (n, mean, standard 
deviation, median, minimum and maximum) will be presented by treatment group for continuous 
variables. Frequencies and percentages will be presented by treatment group for categorical 
variables. 
8.6.1. Analysis Populations 
8.6.1.1 Evaluable Population 
The Evaluable population is defined as the set of subjects who have received at least one dose of 
leronlimab (PRO 140) and have measurable disease at baseline. This population will be used for 
the analysis of efficacy parameters or measurements 
8.6.1.2 Per Protocol Population 
The Per Protocol (PP) population is defined as the set of subjects who meet the Evaluable 
Population requirements and were not associated with any major protocol violations. This 
population will be identified before the database lock. 
The PP analysis of primary and secondary endpoints will be considered supportive 
8.6.1.3 Safety Population 
The Safety Population will include all subjects who have received one dose of leronlimab (PRO 
140). This population will be used for the analysis of safety parameters. 

 
 
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8.6.2. Covariates 
For efficacy analyses, the baseline values will be used as covariates in the analysis models. Other 
important prognostic factors will be specified in the SAP for the study. 
8.6.3. Missing Data 
All data will be used as observed, and no imputations will be made for any missing data point for 
early phase study. 
8.7 
ANALYSIS METHODS 
A SAP will be developed and approved before the database is locked. The SAP will present the 
detailed statistical methodology to be used in analyzing the data from this trial. 
8.7.1. Subject Disposition 
The disposition of all subjects who sign an ICF will be provided. The numbers of subjects 
screened, enrolled, completed, and discontinued during the study, as well as the reasons for all 
post-enrollment discontinuations will be listed and/or summarized by treatment group. 
Disposition and reason for study discontinuation will also be provided as a by-subject listing. 
8.7.2. Demographic and Baseline Disease Characteristics 
Demographics and baseline disease characteristics including medical history, prior and 
concomitant medications/therapies will be listed and/or summarized by treatment group using 
appropriate descriptive statistics. 
8.7.3. Study Analyses 
Safety Outcome Measures: 
The safety outcome measures in this study are: 
 The number, frequency, and severity of adverse events (AEs) collected from the time of 
first treatment until 12 weeks after study treatment completion to evaluate safety of 
leronlimab (PRO 140) in subjects with CCR5+ mTNBC.  
Note: Adverse events will follow National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 
 Laboratory data changes from baseline to subsequent scheduled visits 
 Changes in physical examinations from baseline to subsequent scheduled visits 
 Changes in vital signs from baseline to subsequent scheduled visits. 

 
 
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 Changes in Eastern Cooperative Oncology Group (ECOG) performance status from 
baseline to subsequent scheduled visits. 
 Changes of electrocardiogram (ECG) results from baseline to subsequent scheduled visits 

 
 
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Efficacy Outcome Measures:  
The efficacy outcome measures in this study are: 
 Progression free survival (PFS) defined as time in months from the date of first study 
treatment to the date of disease progression or death from any cause, whichever comes 
first.  
Note: All patients who receive at least one dose of leronlimab (PRO 140) will be included 
in the primary analyses of PFS. The Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1) criteria will be used for objective tumor response assessment (when 
disease is measurable and non- measurable); 
The time in months from start of treatment to progression or death will be measured for 
all patients who receive at least one dose of study drug. Patients will be followed up to 2 
years after completion of treatment. 
 PFS according to RECIST v1.1 in participants with Detectable Programmed Death-Ligand 
1 (PD-L1)  
Note: The PD-L1 expression testing will be performed at baseline. Breast tissue (primary 
or metastatic site) collected to analyze for the presence of CCR5 at pre-screening will 
additionally be used for evaluating PD-L1 expression levels. 
 Overall response rate (ORR, defined as Complete Response (CR) + Partial Response 
(PR)), and clinical benefit rate (CBR, defined as CR + PR + Stable Disease (SD)) in 
subjects with CCR5+ mTNBC treated with leronlimab (PRO 140) combined with a 
treatment of physician’s choice.  
Note: Overall response rate is defined as the proportion of patients who achieve an 
overall response of complete response or partial response in the total number of evaluable 
patients, assessed by RECIST v1.1. Clinical benefit rate is defined as the proportion of 
patients who achieve an overall response of complete response or partial response or 
stable disease in the total number of evaluable patients, assessed by RECIST v1.1. 
Imaging scans to be done approximately every 3 months or according to institution’s 
standard practice. 
 Time to new metastases (TTNM); 
Note: Recorded time from baseline metastatic disease (at time of enrollment) to the time of 
development of new metastasis in different site. New metastases in same site will be also 
recorded. 
 The change from baseline in circulating tumor cells (CTC) level in the peripheral blood. 

 
 
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Note: Reported unit of measure will be the number of CTCs/milliliter. CTCs enumeration 
will be performed at baseline and at the time of response assessment. Fraction of baseline 
positive and change from ≥5 CTCs will be recorded and reported. 
 Overall survival defined as time in months from the date of first study treatment to the 
date of death;  
Note: Patients will be followed from the start of treatment until 2 years post-treatment or 
death, whichever occurs first, and average survival time will be measured. 
Exploratory Outcome (Endpoints) Measures: 
 Measure immune biomarkers (PD-L1) in CTCs, metastatic tissue and immune cells such 
as CAMLs and correlate with therapeutic benefit (PFS); and 
 Correlation between CCR5 expression (CTCs, CAMLs) and PD- L1 expression. 
PFS will be calculated using Kaplan-Meier curves and the median PFS will be read from this 
curve. Response rates (overall response rate, clinical benefit rate) will be calculated using 
proportions and 95% confidence intervals. Time to new metastases and overall survival will also 
be analyzed using Kaplan-Meier curves. Exploratory serial blood markers will be related to PFS 
using Cox regression, and to response using logistic regression. 
8.7.3.1 Safety Analyses  
Safety will be assessed by close monitoring and timely assessment of adverse events (AEs), 
laboratory parameters (blood tests, urinalysis), vital signs (blood pressure, heart rate), subject’s 
medical condition (physical examination including weight), general well-being and activities of 
daily life (Eastern Cooperative Oncology Group (ECOG) performance status). Each subject will 
be regularly assessed at each visit for potential AEs and disease related signs and symptoms. The 
CTCAE v5.0 will be used to grade toxicities / AEs. 
The Safety population will be used for the analysis of safety endpoints.  
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) will be 
calculated for continuous variables. Frequencies and percentages will be presented for categorical 
variables.  
Adverse Events: 
Adverse events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA). Treatment Emergent AE’s (TEAE) are defined as events with an onset on 
or after the first treatment. TEAEs will be summarized by study phase, treatment group, System 
Organ Class, and preferred term. The following TEAE summaries will be provided: 

 
 
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 Overall (i.e., regardless of severity or relationship to treatment) 
 By severity grade (mild, moderate, severe, or life threatening for SAEs) 
 By relationship to clinical trial treatment according to the mapping scheme below: 
o Potentially related: will include all adverse events with a relationship rating of 
“definitely”, “probably” or “possibly”.  
o Unlikely/not related: will include all adverse events with a relationship rating of 
“unlikely” or “unrelated”. 
In addition, separate summaries of serious adverse events, and adverse events resulting in 
discontinuation of study treatment will be presented. 
Clinical Laboratory Data 
All laboratory values will be listed. Laboratory measurements will also be summarized as 
continuous variable and presented by treatment group and time point.  
Physical Examination  
All physical examination findings will be listed and/or summarized.  
Vital Signs 
All vital sign findings will be listed and summarized.  
Electrocardiograms (ECGs) 
All ECG findings will be listed and summarized.  
Eastern Cooperative Oncology Group (ECOG) performance status 
All ECOG performance status findings will be listed and summarized.  
 

 
 
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9 ADVERSE EVENTS (DEFINITIONS AND REPORTING) 
The Investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE, as provided in this protocol. During the study when there is a 
safety evaluation, the Investigator or site staff will be responsible for detecting, documenting and 
reporting AEs and SAEs as detailed in this Section of the protocol.  
9.1 
ADVERSE EVENT (AE)  
An adverse event (AE) is defined as any unfavorable or unintended sign, symptom, or disease that 
occurs or is reported by the subject to have occurred, or a worsening of a pre-existing condition. 
An adverse event may or may not be related to the study treatment.  
AEs will be elicited through direct questioning and subject reports. Any abnormalities in visit 
evaluations, physical examination findings or laboratory results that the investigator believes are 
clinically significant to the research subject and that occurred after initiation of the first study 
treatment will be reported as AEs. Abnormal findings that are NOT clinically significant should 
be not be recorded as an AE  
9.2 
REPORTING AND FOLLOW-UP OF ADVERSE EVENTS 
Report initiation for all AEs and serious adverse events (SAEs), (see Section 9.39.3), will begin at 
the time of the first treatment and continue up to the final study visit. All events will be followed 
to resolution or until 30 days after the subject completes the study. A final assessment of outcome 
will be made at that time. 
All AEs must be recorded in the subject’s medical records and on the CRF. AEs will be reported 
using customary medical terminology along with the following information: the onset and end 
dates, whether the event is considered to be a SAE (see Section 9.39.3), the impact the event had 
on study treatment (see Section 9.2.19.2.1), the CTCAE grade (intensity) of the event (see Section 
9.2.29.2.2), the causality of the event (see Section 9.2.39.2.3), whether treatment was given as a 
result of the event (see Section 9.2.4), and the outcome of the event (see Section 9.2.59.2.5). 
9.2.1. Impact on Study Treatment 
The impact the event had on the study treatment will be assessed as either: none, study treatment 
interrupted, study treatment discontinued, or not applicable. The “not applicable” assessment will 
be used only when the subject is no longer in the treatment period of the protocol or died. 
9.2.2. CTCAE Grade (Intensity) Assessment 
The guidelines outlined in CTCAE v5.0 will be used for assessing the intensity of the event. The 
general guidelines for assessing the AE grade appear below. Full guidelines may be obtained at 

 
 
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5. Definitely – The event follows a reasonable temporal sequence from the study biologic or 
control, abates upon discontinuation and cannot be explained by known characteristics of 
the patient’s clinical state. 
9.2.4. Treatment Given as a Result of the Event 
The event impact in terms of treatment provided will be as either: none, medication administered, 
non-drug therapy administered, surgery performed, hospitalization, or other (with a specification). 
9.2.5. Outcome Assessment 
The outcome of the event will be assessed as either: resolved, resolved with sequelae, ongoing, or 
death. Only one AE per subject is allowed to have an outcome assessment as “death.” If there are 
multiple causes of death for a given subject, only the primary cause of death will have an outcome 
of death.  
9.2.6. Injection-site reactions 
Injection-site reactions thought to be directly related to the injection are considered to be AEs of 
special interest, and will be assessed as per CTCAE v5.0. 
For subjects who develop Grade 1 or Grade 2 events, therapy will be continued as per protocol. If 
a subject chooses to discontinue study treatment, the site should notify the protocol team 
leadership, and encourage the subject to complete any remaining study visits until the toxicity 
resolves. 
For subjects who develop Grade 3 events following study drug injection, the subject should be 
reevaluated closely until the AE returns to Grade 1 or less, at which time study treatment may be 
reintroduced at the discretion of the site investigator. If the same Grade 3 AE recurs following the 
next administration of study drug, study treatment must be permanently discontinued. Subjects 
experiencing Grade 3 AEs requiring permanent discontinuation of study treatment should be 
followed closely for resolution of the AE to Grade 1 or less and the team leadership must be 
notified. 
For Grade 4 events permanently discontinue therapy.  
9.3 
SERIOUS ADVERSE EVENTS 
A SAE is defined as any AE that: 
 Results in death 
 Is life threatening (the subject is at immediate risk of dying from the adverse experience) 
 Requires subject hospitalization or prolongs existing hospitalization 
 Results in persistent or significant disability/incapacity  

 
 
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 Is a congenital anomaly/birth defect 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse device effect when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
9.4 
REPORTING OF SERIOUS ADVERSE EVENTS 
The Investigator is required to report all SAEs that occur during the time period specified in 
Section 9.29.2. Once the Investigator becomes aware of an SAE, he/she must report the SAE to 
Amarex Safety and Pharmacovigilance Department within 24 hours: 
 
CRO Medical Monitor 
 
 
 
 
 
 
 
 
 
 
A written SAE reports must include a full description of the event as described in Section 9.29.2 
and must follow within 24 hours from the time the Investigator first learned of the event. The 
Amarex Medical Monitor may request additional supporting documentation as it becomes 
available, such as lab reports, electrocardiogram [ECG] reports, discharge summary, hospital 
notes, etc, if applicable.  
The Investigator is also responsible for reporting all SAEs to the appropriate Institutional Review 
Board (IRB) in accordance with local laws and regulations. The Investigator is responsible for 
maintaining documentation in the study file that indicates the IRB has been properly notified.  
9.5 
SAE FOLLOW-UP 
All subjects experiencing an SAE, including the discontinued subjects, must be closely followed 
until sufficient information is obtained to indicate a return to normal status or until the event 
stabilizes at a level acceptable to the investigator (i.e., recovery, return to baseline status, no 
further improvement expected, or death). 
For each SAE indicated as an unresolved event on the initial report, regardless of whether the 
subject completed the study or withdrew, the site should submit a follow-up report with updated 
information. 

 
 
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10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Subjects will be identified on eCRFs by a unique subject identification number and on source 
documents by name and date of birth. No personal identifier will be used in any publication or 
communication used to support this research study. The subject identification number will be 
used if it becomes necessary to identify data specific to a single subject.  
The local IRB, FDA, the monitors, auditors and personnel authorized by the Sponsor are eligible 
to review the medical and research records related to this study as part of their responsibility to 
protect human subjects in clinical research. They will be given direct access to source data and 
documentation (e.g., medical charts/records, printouts etc.) for source data verification, provided 
that subject confidentiality is maintained in accordance with local requirements. Access to 
electronic medical records may be governed by institution policy and each site will be required to 
ensure access while remaining compliant with institutional requirements. 
 
 
 

 
 
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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 MONITORING REQUIREMENTS 
The specific obligations outlined in 21 Code of Federal Regulations (CFR) and ICH guidelines 
require the Sponsor to maintain current personal knowledge of the progress of a study. Therefore, 
the Sponsor's designated monitor will visit the site during the study as well as maintain frequent 
telephone and written communication. The Investigator will permit the Sponsor to monitor the 
study as frequently as is deemed necessary and provide access to medical records to ensure that 
data are being recorded adequately, that data are verifiable and that protocol adherence is 
satisfactory.  
As delineated above, the Investigator will permit representatives of the Sponsor and/or designated 
CRO to inspect all CRFs and corresponding study subject original medical records (source 
documents) at regular intervals throughout the study. Subject original medical records and other 
relevant data must be available to support all data recorded in the eCRF. In addition to the 
original medical records, these data may include but are not limited to study, laboratory reports, 
etc.  
In accordance with federal regulations, site inspections will serve to verify strict adherence to the 
protocol and the accuracy of the data that is being entered on the case report forms. A Monitoring 
Log will be maintained at each study site. The Monitoring Log will be signed by the monitor, 
dated and stated the type of visit. The Investigator should be aware that the study site and subject 
records may be inspected by the Sponsor and or representatives of the designated CRO, FDA or 
other regional regulatory authority. 
11.2 ACCEPTABILITY OF CASE REPORT FORMS (CRFS) 
For each subject who has signed an informed consent form, a CRF must be completed. For 
subjects who are screen failures, this would be limited to the screen failure CRF page. All source 
documents and CRFs will be completed as soon as possible after the subject's visit and 
corrections to data on the CRFs will be documented, if applicable. The Investigator will review 
the CRFs to indicate that, to his/her knowledge, they are complete and accurate. CRFs will be 
reviewed by the Sponsor’s or designated CRO’s monitor, who will make a decision as to their 
acceptability.  
 
 
 

 
 
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11.3 MODIFICATION OF PROTOCOL 
The Investigator will not modify or alter this protocol without first obtaining the concurrence of 
the Sponsor. Approval by the Investigator’s IRB must also be obtained prior to implementation of 
the change, with two exceptions: 
1. When necessary to eliminate apparent immediate hazard to the subject; or 
2. When the modification does not involve the subject’s participation in the trial. 
An amendment may also require modification of the informed consent form. The Investigator will 
provide an approval letter for the amendment and revised informed consent form, if applicable, to 
the Sponsor. An amendment must be provided in writing and it must be dated by both the Sponsor 
and the Investigator. If necessary, the Sponsor will submit protocol amendments to FDA and 
other appropriate regulatory authorities and notify other Investigators using this protocol. 
11.4 REPORTING PROTOCOL DEVIATIONS 
The Investigator is obligated to follow the protocol without departure from the requirements 
written in the protocol. If the Investigator deviates from the protocol requirements, the Sponsor 
will make the determination as to whether the subject will continue in the study. The Sponsor also 
has the right to discontinue the subject for protocol violations. The IRB may also have to be 
contacted if safety to the subject or if the scientific soundness of the study is involved. All 
protocol deviations must be documented in the CRFs. 
11.4.1. Major Protocol Deviation or Violation 
A major protocol deviation or violation is a deviation from the IRB approved protocol that may 
affect the subject's rights, safety, or well being and/or the completeness, accuracy and reliability 
of the study data. Examples of this include: 
 Failure to obtain informed consent prior to initiation of study-related procedures  
 A research subject does not meet the protocol's eligibility criteria but was enrolled without 
prior approval from the sponsor. 
 A research subject received the wrong treatment or incorrect dose. 
 A research subject met withdrawal criteria during the study but was not withdrawn. 
 A research subject received a prohibited concomitant medication. 
 Failure to treat research subjects per protocol procedures that specifically relate to primary 
efficacy outcomes. 
 Changing the protocol without prior sponsor and IRB approval. 

 
 
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 Multiple minor violations of the same nature after multiple warnings. 
11.4.2.  Minor Protocol Deviation or Violation 
A minor protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that has not been approved by the IRB and which DOES NOT 
have a major impact on the subject's rights, safety or well-being, or the completeness, accuracy 
and reliability of the study data. Examples of this include: 
 Follow-up visits that occurred outside the protocol required time frame because of the 
participant’s schedule. 
 Blood samples obtained at times close to but not precisely at the time points specified in 
the protocol. 
 
 
 

 
 
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12 DATA SAFETY MONITORING BOARD (DSMB) 
The study will be monitored by an independent DSMB to ensure patient safety. The CRO is 
responsible for the overall management of DSMB, including development of its charter and 
membership selection. The DSMB will be managed in conformance with the FDA guidelines 
for DSMB independence, management, and oversight. 
The DSMB will consist of at least three members and will review unexpected AEs, related AEs, 
SAEs, and deaths, according to the study’s phase and risk level, as outlined in the DSMB 
charter. 
All expedited safety reports will be provided in real time to the DSMB chair upon being 
reported to FDA. 
Note: For the purpose of expedited safety reporting, all adverse events except skin reactions will 
be considered unexpected. 
 The DSMB will make the following recommendations at each safety evaluation: 
 Continue the study as planned; 
 Assess a specific aspect of safety that is not conclusive; 
 Gather more data to address a specific safety issue; and 
 Stop the study due to safety concerns. 
Additionally, DSMB may recommend protocol modifications or other actions including but not 
limited to the following: 
 Discontinuing or modifying a study based on safety information obtained from the protocol 
or from information external to the trial 
 Changing the eligibility criteria if the risks of the intervention appear to be higher in a 
particular subset of patients 
 Altering the drug dosage and/or schedule if the adverse events observed appear likely to be 
mitigated by such changes 
 Instituting screening procedures that could identify those subjects at increased risk of a 
particular adverse event 
 Identifying information needed to inform current and future trial subjects of newly identified 
risks via changes in the informed consent document and, if appropriate, recommending re-
consent of current subjects to continue trial participation. 
The Sponsor retains the responsibility to contact FDA and the final decision regarding the 

 
 
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recommendation to continue or to terminate the study. 

 
 
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13 ETHICS AND REGULATORY REQUIREMENTS 
This study is to be conducted in accordance with the specifications of this protocol and in 
accordance with principles consistent with Declaration of Helsinki, GCP, 21 CFR, ICH E6, 
HIPAA regulations in 45 CFR Part 164 (US only), and the Belmont Principles of respect for 
persons, beneficence, and justice. No protocol changes will be implemented without the prior 
review and approval of the IRB, except when the modification does not involve the subject’s 
participation in the trial or where it may be necessary to eliminate an immediate hazard to a 
research subject. In the latter case, the change will be reported to the IRB as soon as possible, 
according to IRB regulations.  
Additionally, the study product used in this study is manufactured, handled and stored in 
accordance with applicable GMP. The study product provided for this study will be used only in 
accordance with this protocol. 
13.1 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
The Principal Investigator (PI) at the site will provide the Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) with all appropriate materials as required by their IRB/IEC, 
including but not limited to the clinical study protocol, informed consent form, and any 
advertising materials. The study will not be initiated until the IRB/IEC provides written approval 
of the aforementioned documents and until approval documents have been obtained by the 
Principal Investigator and Sponsor or Sponsor designee. The Investigator will not participate in 
the decision. If the Investigator is an IRB or IEC member, documentation must be provided 
indicating recusal from the approval process. Appropriate reports on the progress of this study by 
the Principal Investigator will be made to the IRB/IEC as required by local and applicable 
government regulations and in agreement with policy established by the Sponsor. The 
Investigator is required to maintain an accurate and complete record of all written correspondence 
to and received from the IRB/IEC, and must agree to share all such documents and reports with 
the Sponsor. 
No changes from the final approved protocol will be initiated without the IRB/IEC’s prior written 
approval or favorable opinion of a written amendment, except when necessary to eliminate 
immediate hazards to the subjects or when the modification does not involve the subject’s 
participation in the trial.  
13.2 INVESTIGATOR’S RESPONSIBILITIES 
The Investigators are responsible for performing the study in full accordance with the protocol 
and the current revision of the Declaration of Helsinki, the Good Clinical Practice: Consolidated 

 
 
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Guideline, approved by the ICH, and any applicable national and local laws and regulations. 
Information regarding to the study center participating in this study that cannot comply with these 
standards will be documented. 
13.3 SUBJECT INFORMED CONSENT REQUIREMENTS 
All subjects participating in this study will be given to by the Investigator and/or designee, written 
and oral information about the study in a language understandable by the subject. Written 
informed consent will be obtained from each subject prior any procedures or assessments that 
would not otherwise be required for the care of the subject are done and after the aims, methods, 
anticipated benefits, potential hazards, and insurance arrangements in force are explained and the 
subject has been given sufficient time to ask questions and consider participation in the study. It 
will also be explained to the subjects that they are free to refuse entry into the study and free to 
withdraw from the study at any time without prejudice to future treatment. It is permissible for a 
third person (e.g., a family member) to be present during the explanation of the study. 
The written Informed Consent Form ICF will be in compliance with CFR 21 Part 50.27 and GCP 
guidelines. The Sponsor and/or designated CRO will approve the ICF and all amendments to the 
ICF prior to submission to the IRB/IEC. A copy of the ICF to be used will be submitted by the 
Investigator to the IRB/IEC for review and approval prior to the start of the study. The study site 
must provide the Sponsor with an unsigned copy of IRB/IEC-approved ICF along with applicable 
documentation to support this approval. The original signed ICF is retained in the subject's study 
records, and a copy is provided to the subject. A second copy may be filed in the subject’s 
medical record, if allowed by institutional policy.  
 

 
 
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14 DATA HANDLING AND RECORD KEEPING 
14.1 RECORDING AND COLLECTION OF DATA 
The primary source document for this study will be the subject's medical record. If separate 
research records are maintained by the Investigator(s), the medical record and the research 
records will be considered the source documents for the purposes of auditing the study.  
Applicable source data will be manually transcribed to approve case report forms (CRF). The 
Investigator is ultimately responsible for the accuracy of the data transcribed on the forms. All 
source documents and CRFs will be completed as soon as possible after the subject's visit. 
The Investigator will review the CRFs to indicate that, to his/her knowledge, they are complete 
and accurate. Designated source documents will be signed and dated by the appropriate study 
personnel. The Investigator must agree to complete and maintain source documents and CRFs for 
each subject participating in the study. 
All research data will be entered, either electronically or manually, into a computerized database. 
The clinical database will be designed by the clinical data manager in accordance with 21 CFR 
Part 11 and based on protocol requirements defined by the Sponsor in association with the Lead 
Investigator.  
The Investigator will maintain a confidential list of study subjects that will include each subject’s 
study number, name, date of birth, and unique hospital identification number if applicable. This 
list will be kept by the Investigator and will not be collected by the Sponsor. A notation will be 
made in the subject’s case history/medical chart that he/she is participating in a clinical study and 
has provided a signed and dated ICF as well as a release for protected health information as 
required by local policies. The Investigator must also maintain a separate screening log of all the 
subjects screened for participation in the study; it should include gender, age, eligibility status, 
reason for ineligibility, if applicable; and study allocated subject number, if applicable.  
14.2 CLINICAL DATA MANAGEMENT 
The Sponsor and/or designated CRO will be responsible for the processing and quality control of 
the data. Data management will be carried out as described in the Sponsor’s or CRO’s standard 
operating procedures (SOPs) for clinical studies. 
The handling of data, including data quality control, will comply with regulatory guidelines 
(e.g., ICH E6 GCP, and local regulations where applicable) and the Sponsor’s or the CRO’s SOPs 
as well as provisions of the study-specific Data Management Plan. 
 

 
 
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14.3 ARCHIVING 
All study documentation at the Investigator site and Sponsor site will be archived in accordance 
with ICH GCP E6 and the Sponsor’s quality standards and SOPs. 
The Investigator will maintain all research records, reports, and case history reports for a period 
of two (2) years after regulatory approval of the investigational product. If no application is filed 
or if the application is not approved, records must be maintained for two (2) years after all 
investigations have been completed, terminated or discontinued and the FDA has been notified.  
These documents should be retained for a longer period however, if required by the applicable 
regulatory requirements or if needed by Sponsor or its authorized representative (as per 
GCP 5.5.11). 
At the completion of the study, details of the archival process must be provided to the Sponsor. 
Study records are subject to inspection by applicable health and regulatory agencies at any time.  
Records to be retained by the Investigator include, but are not restricted to: 
 Source data and the primary records upon which they are based (e.g., subject’s progress 
notes, adverse event data, test results, and any other diagnostic procedures required to 
evaluate the progress of the study) 
 Completed CRFs 
 Signed protocols and protocol amendments 
 Laboratory results, ranges, and certifications 
 IP and accountability records 
 Study personnel signature log 
 Monitoring logs 
 Correspondence to and from the Sponsor, designee and IRB 
 Investigator and sub-investigator CVs 
 Signed informed consent and protected health information consent forms 
 Subject screening  
 SAE reports 
 IRB approval and re-approval letters 
 Completed quality of life questionnaire 
 Other documents pertaining to the conduct of the study 
These documents must be maintained and kept on file by the Investigator so that the conduct of 
the study can be fully documented and monitored. 

 
 
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Study records should not be transferred from site or destroyed without prior written agreement 
between the Sponsor and the study Investigator. Study records are subject to inspection by 
applicable health and regulatory agencies at any time.  
 
 

 
 
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15 PUBLICATION PLAN 
All information supplied by CytoDyn in connection with this study and not previously 
published, is considered confidential information. This information includes, but is not 
limited to, the Investigator’s Brochure, clinical protocol, case report forms and other scientific 
data. Any data collected during the study are also considered confidential. This confidential 
information shall remain the sole property of CytoDyn, shall not be disclosed to others 
without the written consent of CytoDyn, and shall not be used except in the performance of this 
study. 
It is understood by the Investigator that the Sponsor will use the information collected in this 
clinical trial in connection with the development of CytoDyn. Therefore, this information may be 
disclosed as required to other Investigators or appropriate regulatory authorities. By agreeing to 
participate in this clinical trial, the Investigator understands that he/she has an obligation to 
provide the Sponsor with complete test results and all data developed during this trial. 
Publication and Disclosure: The site and Investigator agree to submit any proposed manuscript, 
presentation or other public disclosure regarding the study to Sponsor for review at least thirty 
(30) days prior to submitting such proposed manuscript to a publisher or delivering or making 
such presentation or other public disclosure to any third party. Within thirty (30) days of its 
receipt, Sponsor shall advise the site and/or Investigator, as the case may be, in writing of any 
information contained therein that is confidential information (other than research results included 
in a proposed manuscript) or that may impair Sponsor’s ability to obtain patent protection. 
Sponsor shall have the right to require the site and/or Investigator, as applicable, to remove 
specifically identified confidential information (but may not require removal of research results 
from a proposed manuscript) and/or to delay the proposed submission or delivery of the proposed 
manuscript or presentation, or other public disclosure, for an additional sixty (60) days to enable 
Sponsor to seek patent protection. The site and Investigator shall not publish, publicly disclose, 
present or discuss any results of or information pertaining to the site’s and Investigator’s activities 
prior to completion of the trial, even if the multi-center trial or the study is terminated before its 
completion and the final clinical study report is signed off, or with respect to any endpoints or 
analyses other than those specified in this protocol. 

 
 
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16 REFERENCES 
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Chumsri S, Tang CM, Cristofanilli M.  Circulating giant macrophages as a potential biomarker of 
solid tumors. PNAS 2014;111:3514–3519. 
Adams DL, Adams DK, He J, Kalhor N, Zhang M, Xu T, Gao H, Reuben JM, Qiao Y, Komaki R, 
Liao Z,  Edelman MJ, Tang C-M, Lin SH, Sequential tracking of PD-L1 expression and RAD50 
induction in circulating tumor and stromal cells of lung cancer patients undergoing radiotherapy,  
Clinical Cancer Research, 2017; 23:5948-5959. 
Adams DL, Adams DK, Lin SH, Cristofanilli M, Bergan RC, Marks J, Martin SS, Chumsri S, Ho 
TH, Lapidus RG, Tsai S, Tang CM, Katherine Alpaugh RK, Cancer-associated macrophage-like 
cells as prognostic indicators of overall survival in a variety of solid malignancies.  Power Point 
presentation on ASCO website. https://meetinglibrary.asco.org/results/adams%20caml;page=1 
Al-Kateb H, Nguyen TT, Steger-May K, Pfeifer JD. Identification of major factors associated 
with failed clinical molecular oncology testing performed by next generation sequencing (NGS). 
Molecular oncology. 2015 Nov 1;9(9):1737-43. 
Bidard FC, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, 
Garcia-Saenz JA, Stebbing J, Caldas C. Clinical validity of circulating tumour cells in patients 
with metastatic breast cancer: a pooled analysis of individual patient data. The Lancet Oncology. 
2014 Apr 1;15(4):406-14. 
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, 
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Allard WJ, Terstappen LW, Hayes DF. Circulating tumor cells, disease progression, and survival 
in metastatic breast cancer. New England Journal of Medicine. 2004 Aug 19;351(8):781-91. 

 
 
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to the tumor microenvironment contributes to skin squamous cell carcinoma development. 
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17 APPENDIX 
17.1 APPENDIX 1:  ACCEPTABLE METHODS OF CONTRACEPTION 
 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
 Male 
condom 
plus 
spermicide 
 Cap plus spermicide 
 Diaphragm 
plus 
spermicide 
 Copper T 
 Progesterone T 
 Levonorgestrel-releasing 
 Implants 
 Hormone shot or 
injection 
 Combined pill 
 Minipill 
 Patch 
NOTE: choice of contraception should be discussed with primary treating oncologist to 
discuss the risks and benefits of different modalities of contraception.

 
 
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17.2 APPENDIX 2: RECOMMENDATIONS FOR HER-2 TESTING IN BREAST CANCER 
Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: 
American Society of Clinical Oncology/College of American Pathologists clinical practice 
guideline update. 
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett 
JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, 
Spears PA, Vance GH, Viale G, Hayes DF; American Society of Clinical Oncology; College of 
American Pathologists. 
J Clin Oncol. 2013 Nov 1;31(31):3997-4013. doi: 10.1200/JCO.2013.50.9984. Epub 2013 Oct 7. 
 
For complete detailed information please refer to the link below: 
http://ascopubs.org/doi/full/10.1200/JCO.2013.50.9984 

 
 
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17.3 APPENDIX 3: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V5.0 
 
For complete detailed information please refer to the link below: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Re
ference_8.5x11.pdf