A Phase II Study of sEphB4-HSA in Metastatic Castration-Resistant Prostate Cancer
Phase: PHASE2
Conditions: Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Castration-Resistant Prostate Carcinoma Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents, Metastatic Prostate Adenocarcinoma, Progressive Disease, Prostate Carcinoma Metastatic in the Bone, Prostate Carcinoma Metastatic in the Soft Tissue, PSA Progression, Stage IVB Prostate Cancer AJCC v8, Testosterone Less Than 50 ng/dL
Sponsor: Northwestern University

NU Study Number: NU 18U10
CONFIDENTIAL
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. 
Do not disclose or use except as authorized in writing by the study sponsor.
A Phase II study of sEphB4-HSA in metastatic castration-
resistant prostate cancer 
Principal investigator: 
Maha Hussain, MD
Robert H Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of Medicine
Chicago, IL 60611
Phone: 312-908-5487
Fax: 312-908-1372
Email: mhussain@northwestern.edu
Co-investigator:
Sarki Abdulkadir, MD
Northwestern University
Robert H Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of 
Medicine
Chicago, IL 60611
Email: sarki.abdulkadir@northwestern.edu
NU-LCC Co-investigator:
Alicia Morgans, MD
Northwestern University 
Robert H Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of Medicine
Chicago, IL 60611
Email: alicia.morgans@northwestern.edu
NU-LCC Co-investigator:
David VanderWeele, MD, PhD
Northwestern University 
Robert H Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of 
Medicine
Chicago, IL 60611
Email: david.vanderweele@northwestern.edu
University of Southern California Co-investigator:
David Quinn, MBBS, PhD
The University of Southern California
1441 Eastlake Ave Ste 7310
Los Angeles CA 90033 USA
Email: diquinn@usc.edu
University of Chicago Co-investigator:
Walter M. Stadler, MD
The University of Chicago
5841 S. Maryland Avenue, MC 2115 
Chicago, IL 60637
Email: wstadler@medicine.bsd.uchicago.edu
Biostatistician:
Borko Jovanovic, Ph.D.
Northwestern University 
Robert H Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of Medicine
Chicago, IL 60611
Email: borko@northwestern.edu
Study Intervention(s):
sEphB4-HSA
IND Number:
143436
IND Holder:
Maha Hussain, MD
Support for drug:
VasGene Therapeutics Inc
Version Date:
September 18, 2020 (Amendment 6) 
Coordinating Center:
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
http://cancer.northwestern.edu/CRO/index.cfm
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................................4
STUDY SCHEMA ............................................................................................................................5
STUDY SUMMARY .........................................................................................................................6
1.0
INTRODUCTION – BACKGROUND & RATIONALE ...........................................................11
1.1
Disease background......................................................................................................11
1.2
Ephrins background & overview....................................................................................11
1.3
Summary of pre-clinical findings of EphB4 in prostate cancer ......................................11
1.4
sEphB4-HSA .................................................................................................................13
1.5
Summary of clinical trial findings ...................................................................................13
1.6
Rationale for the Current Study.....................................................................................14
1.7
Rationale for Exploratory Studies..................................................................................14
2
OBJECTIVES........................................................................................................................15
2.1
Primary Objective: .........................................................................................................15
2.2
Secondary Objectives:...................................................................................................15
2.3
Exploratory Objectives:..................................................................................................15
3
PATIENT ELIGIBILITY..........................................................................................................15
3.1
Inclusion Criteria............................................................................................................15
3.2
Exclusion Criteria...........................................................................................................17
4
TREATMENT PLAN..............................................................................................................18
4.1
Overview........................................................................................................................18
4.2
Treatment Administration ..............................................................................................19
4.3
Toxicity Management & Dose Delays/Modifications......................................................20
4.4
Concomitant Medications/Treatments ...........................................................................23
4.5
Duration of Therapy.......................................................................................................24
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4.6
Duration of Follow Up....................................................................................................24
4.7
Removal of Subjects from Study Treatment and/or Study as a Whole .........................24
4.8
Patient Replacement .....................................................................................................24
5
STUDY PROCEDURES ........................................................................................................25
6
ENDPOINT ASSESSMENT ..................................................................................................29
6.1
Definitions......................................................................................................................29
6.2
Assessment of primary endpoint ...................................................................................33
6.3
Assessment of secondary endpoints.............................................................................33
6.4
Exploratory Endpoints ...................................................................................................34
7
ADVERSE EVENTS..............................................................................................................34
7.1
Adverse Event Monitoring .............................................................................................34
7.2
Definitions & Descriptions..............................................................................................34
7.3
Adverse Event Reporting...............................................................................................36
8
DRUG INFORMATION..........................................................................................................37
8.1
sEphB4-HSA .................................................................................................................37
9
CORRELATIVES/SPECIAL STUDIES .................................................................................40
9.1
Description of Correlative studies:.................................................................................40
9.2
Sample Collection Guidelines........................................................................................42
9.3
Sample Processing, Storage, and Shipment.................................................................42
9.4
Assay Methodology .......................................................................................................42
9.5
Specimen Banking.........................................................................................................42
10
STATISTICAL CONSIDERATIONS......................................................................................42
10.1
Sample size and Statistical and data analysis plan for the primary objective. ..............42
10.2
Analysis of secondary and exploratory objectives.........................................................43
10.3
Accrual...........................................................................................................................43
11
STUDY MANAGEMENT .......................................................................................................43
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11.1
Institutional Review Board (IRB) Approval and Consent...............................................43
11.2
Amendments .................................................................................................................44
11.3
Registration Procedures................................................................................................44
11.4
Data Submission ...........................................................................................................44
11.5
Data Management and Monitoring/Auditing ..................................................................44
11.6
Adherence to the Protocol.............................................................................................45
11.7
Investigator Obligations.................................................................................................45
11.8
Publication Policy ..........................................................................................................45
12
APPENDICES .......................................................................................................................49
12.1
Appendix I: ECOG Performance Status ........................................................................49
12.2
Appendix II: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ...........50
12.3
Appendix III: Highly Effective Methods of Contraception...............................................51
12.4
Appendix IV: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1..................52
12.5
Appendix V: Summary of Changes ...............................................................................53
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LIST OF ABBREVIATIONS
ADT
Androgen Deprivation Therapy
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AR
Androgen Receptor
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTC
Circulating tumor cell
cfDNA
Cell Free DNA
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
H&PE
History & Physical Exam
IV (or iv)
Intravenously
MTD
Maximum Tolerated Dose
mCRPC
Metastatic Castration Resistant Prostate Cancer
NCI
National Cancer Institute
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
WBC
White Blood Cells
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STUDY SCHEMA
   
1.
Beginning at Cycle 7, cycle length will be 21 days and patients will return for treatment on Day 1 of 
each cycle.
Patient population: 
mCRPC 
(after treatment with 2nd generation AR 
targeted therapy and/or chemotherapy for 
metastatic disease)
Patient screening: 
H&P, laboratory tests, imaging, ECG, 
cfDNA 
Treatment: 
(continue ADT) + sEphB4-HSA 1000mg IV
 day 1 of 14-day cycle1
Response assessment: 
PSA: Day 1 of odd cycles 
Imaging: After 2 months of therapy and every 3 months 
thereafter (after 1 year, patients with stable disease or better 
may have imaging every 4 months)
CR/PR/SD 
continue sEphB4-
HSA d1 q14 days1
Once off treatment continue 
follow-up for 4 weeks or 
resolution/stabilization of AE. 
If stop treatment before objective 
progression, follow up every 6 mo, 
until objective progression, starts 
alternative treatment or 1 year 
(whichever comes first)
Disease progression, 
unacceptable AE or 
other cause for 
discontinuation 
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STUDY SUMMARY
Title
A phase II study of sEphB4-HSA in metastatic castration-resistant 
prostate cancer (mCRPC)
Version
September 18, 2020 (Amendment 6)
Study Design
A phase II, single-arm, open-label, three center study
Study Center(s)
Northwestern University – Robert H. Lurie Cancer Center
University of Chicago
University of Southern California
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Background and rationale:
There is a critical need for novel targets in lethal prostate cancer. Prostate cancer is the third most 
common cause of cancer death for men in the United States [1]. Although 90% of men who receive 
androgen deprivation therapy (ADT) for metastatic disease initially respond, the development of 
metastatic castration-resistant prostate cancer (mCRPC) is almost universal within 2-3 years [2]. 
Standard therapy for mCRPC includes receptor (AR) targeted agents (i.e. abiraterone and 
enzalutamide), microtubule inhibiting chemotherapy (docetaxel and cabazitaxel), and in select 
circumstances sipuleucel-T or radium-223. The median overall survival (mOS) benefit for each of 
these therapies is 2-5 months and mOS is about 3 years for patients with mCRPC [3-9]. Unfortunately, 
response rates, progression free survival (PFS), and mOS drops substantially with subsequent lines of 
therapy. PSA response rate in patients receiving enzalutamide after abiraterone and docetaxel is 10-
15% [10]. Median OS for 2nd, 3rd, and 4th line therapy is 21, 11, and 5 months, respectively [11].
Ephrins and their receptors are potential targets for therapy in mCRPC. Ephrin receptors and their 
membrane-localized ligands induce bidirectional signaling and facilitate tumor-stroma interactions. The 
ephrin pathway impacts a multitude of cellular processes such as cell survival and proliferation, 
neoangiogenesis, and immune development and trafficking [12]. EphB4-ephrinB2 interaction can lead 
to T-cell suppression with immune evasion and EphB4 interacts with PI3K/AKT and MAPK pathways 
[12-15]. Dysregulation of the Ephrin/Eph receptor pathway in prostate cancer cells can promote cell 
migration, invasion, and metastases [16]. Expression of EphB4 is increased in prostate cancer tissue 
and cell lines and retained in castration resistant states but not commonly expressed in benign 
prostate tissue [17, 18]. 
EphB4 inhibition can cause tumor regression in preclinical aggressive prostate cancer models. EphB4 
is induced by molecular alterations implicated in aggressive CRPC development, including loss of the 
tumor suppressor genes, PTEN and TP53, and activation of the PI3K pathway [17]. Experiments from 
Dr. Parkash Gill at the University of Southern California and Dr. Abdulkadir at Northwestern University 
show its inhibition with a soluble EphB4-albumin fusion antagonist led to tumor regression in 10 of 10 
MYC+/PTEN loss/P53 loss mice with prostate cancer. It also induced tumor cell death, and induced 
immune cell infiltration. PTEN and TP53 loss are frequent molecular aberrations in CRPC [19].
An EphB4 antagonist (sEphB4-HSA) was safe and tolerable in a phase I trial in advanced solid 
tumors. Four of 70 patients had a partial or complete response and 50% showed stable disease. 
There were no grade 4 or 5 related adverse events. The most common grade III toxicities were 
hypertension (27%), fatigue (16%), nausea (4%). Grade I/II toxicities included hypertension, fatigue, 
weight loss, and nausea. A dose limiting toxicity of QTC prolongation occurred in one patient at 
10mg/kg IV in the weekly dosing cohort and of hypertension at 20mg/kg IV in the every 2 weeks 
cohort. A maximum tolerated dose was not reached.
Study proposal and hypothesis: We propose study evaluating the efficacy, safety, and tolerability of 
sEphB4-HSA in patients with mCRPC with evaluation of correlative biomarkers. Our hypothesis is 
EphB4-EphrinB2 pathways are active and pathogenic in aggressive mCRPC, and are a therapeutic 
target. 
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Objectives
Primary Objective:
1.
To assess the  efficacy of sEphB4-HSA in patients with mCRPC as 
measured by confirmed PSA response rate
Secondary Objectives:
1.
Safety and tolerability of sEphB4-HSA in patients with mCRPC 
according to NCI CTCAE v 5.0
2.
Time to PSA progression
3.
Overall response rate in patients with measurable disease using 
RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria. 
4.
Radiological progression free survival (rPFS) using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria.
Exploratory Objectives: 
1.
Molecular changes associated with EphB4 and ephrinB2 expression 
in tumor specimens. 
2.
Association of response with molecular biomarkers including 
aberrations in the PI3K pathway, MYC and TP53.
3.
To assess immune cell infiltration of tumors in biopsies
4.
To assess circulating immune changes associated with treatment.
Endpoints
Primary endpoint:
1.
PSA response by PCWG3  criteria
Secondary endpoints:
1.
Toxicity rate and severity by CTCAE v 5.0
2.
Time to PSA progression by PSA response criteria (PCWG3)
3.
Overall response by RECIST 1.1 (soft tissue) and PCWG3 (bone) 
criteria. 
4.
rPFS by RECIST 1.1 (soft tissue) and PCWG 3 (bone) criteria. 
Exploratory endpoints:
1.
IHC staining for expression of EphB4 and ephrinB2 in tumor samples 
and correlate the level of alteration with the MYC, PTEN/PI3K, AR, 
and p53 pathways.
2.
Analysis of cfDNA for mutations in PI3K pathway, MYC or TP53.
3.
IHC for CD3, CD4, CD8, NK cell markers and PD-L1.  
Sample Size
15 patients in stage one + 10 patients in stage 2 for a total of 25 
evaluable patients.
Approximately 4-8 eligible patients are seen per month with an 
anticipated at least 1-2 patient enrolled per month. We expect it will take 
18 months to accrue our study population.
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Diagnosis & Key 
Eligibility Criteria
Inclusion Citeria

Patients must have pathologically confirmed diagnosis of prostate 
adenocarcinoma 

Patients must have metastatic (M1) disease as evidenced by soft 
tissue and/or bony metastases on CT or MRI scan or technetium 
bone scan. 

Patients must have castration resistant disease with disease 
progression despite castrate levels of testosterone (testosterone 
< 50 ng/dL)
Exclusion Criteria

Patients who have had radiotherapy ≤14 days prior to entering 
the study are not eligible.

Patients who have had systemic therapy for prostate cancer ≤21 
days or 5-half lives (whichever is shorter) are not eligible. 
Note: Patients can receive a stable dose of 
bisphosphonates for bone metastases, including 
zoledronic acid, or denosumab before and during the 
study as deemed appropriate by the treating physician. 

Patients receiving any other investigational agents are not 
eligible.
See section 3.0 for complete list
Treatment Plan
sEphB4-HSA will be administered as an IV infusion over 60 minutes on 
day 1 of each cycle (1 cycle = 14 days) along with continued androgen 
deprivation therapy (ADT).   Beginning at Cycle 7, cycle length will be 21 
days and patients will return for treatment on Day 1 of each cycle. 
Patients may continue to receive sEphB4-HSA treatment until no longer 
clinically benefiting (PCWG3), unacceptable toxicity, treatment delay ≥4 
weeks, or prohibitive illness/change in patient’s condition, or patient 
decides to withdraw from study. Response assessment with PSA will 
occur on Day 1 of odd cycles (every 28 days). Imaging will occur at 
baseline and 2 months after starting therapy; thereafter, imaging will be 
conducted every 3 months. After 1 year, imaging can be done every 4 
months for patients with stable disease or better. Scans may also be 
conducted at any time, if clinically indicated. Once off treatment continue 
follow-up for 4 weeks or resolution/stabilization of AE ≤ Grade 1. If off 
treatment before progressive disease, patients will be followed every 6 
months, until objective progression or starts alternative therapy for a 
maximum of 1 year. 
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Statistical Methodology
To estimate preliminary efficacy we will assess PSA response rate (PR 
and CR) with a Simon two stage minimax design. We assume the 
undesirable overall response rate (null hypothesis) to be approximately 
10% or less, and the alternate hypothesis suggesting success to be 
approximately 30% or more. Fifteen patients will be added in the first 
stage. If 2 or more respond, then an additional 10 patients will be added 
for a total of 25 evaluable patients. If not, we will stop the study after the 
first stage.  The study will be assessed by the DSMC for excess toxicity at 
this point in time and stopped if DSMC finds excessive toxicity.  If the 
second stage is completed, five or fewer successes will suggest failure 
and six or more responses a success of the entire study. This design has 
a Type I error rate of less than 5% and 80% or greater power. It has a 
55% chance of stopping early after the first stage if the true response rate 
is 10% or less, and a total expected long run average sample size of 
n=19.5. 
To estimate time to PSA progression, rPFS, and overall survival, we 
will use Kaplan Meier methods. To estimate overall response rate in 
patients with measurable disease using RECIST 1.1 (soft tissue) and 
PCWG3 (bone) criteria, and radiological progression free survival (rPFS) 
using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria we will use 
exact point estimation.
All adverse events (AEs) will be summarized using frequencies and 
percentages. Data on type, timing, frequency and attribution of AEs will 
be included.
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1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Disease background
Prostate cancer causes an estimated 26,730 deaths in 2017, making it the third most 
common cause of cancer death in the United States [20]. Metastatic disease is initially treated 
with androgen deprivation therapy with or without the addition of docetaxel or abiraterone [21, 
22]. Although 90% of men with metastatic prostate cancer who receive androgen deprivation 
therapy (ADT) initially respond, the development of castration-resistant prostate cancer 
(CRPC) is common within 2-3 years, with a subset of patients following an even more 
aggressive course [1, 2]. For patients with metastatic CRPC (mCRPC) standard of care 
treatments include second generation AR targeted therapy (i.e. abiraterone and 
enzalutamide), chemotherapy (docetaxel and cabazitaxel), and in select circumstances 
sipuleucel-T or radium-223. The median overall survival (OS) benefit for each of these 
therapies is less than 6 months, and median OS is under 3 years for patients with mCRPC [3-
9]. PSA response rate in patients receiving enzalutamide after abiraterone and docetaxel is 
10-15% [10]. These results highlight the critical need to advance the understanding of disease 
biology and identify novel therapeutic targets for mCRPC. 
1.2
Ephrins background & overview
Research investigating active pathways in aggressive prostate cancers has identified ephrins 
and their receptors (receptor tyrosine kinases) as potential targets for therapy in advanced or 
aggressive prostate cancer. Ephrin receptors and their membrane-localized ligands induce 
bidirectional signaling with downstream effects on several pathways including MAPK, 
PI3K/AKT, and VEGF. They are involved in multitude of cellular processes such as cell 
survival and proliferation, neoangiogenesis, and immune development and trafficking [12]. 
Additionally, ephrins impact tumor microenvironment and immunogenicity, such that ephrin-
B2 on mesenchymal stromal cells interacts with EphB4 on T cells leading to T-cell 
suppression and potential immune evasion [14, 15]. EphB4 interacts with the PI3K/AKT and 
MAPK pathways that modulate androgen receptor (AR) signaling [12, 13]. Dysregulation of 
the Ephrin/Eph receptor pathway in prostate cancer cells can promote cell migration, invasion, 
and metastases [16]. 
The expression of EphB4 in human tumors has been analyzed with an immunostaining assay. 
Fresh frozen tumor samples and, when possible, adjacent normal tissues were analyzed for 
EphB4 expression using the EphB4-specific monoclonal antibody MAb131. EphB4 expression 
was induced in many of the epithelial cancers analyzed. For example, EphB4 is not 
expressed in the normal bladder and colon, but is highly expressed in the bladder and colon 
tumors. EphB4 expression was observed in breast, head and neck, ovarian, and prostate 
cancers. EphB4 gene amplification was analyzed in head and neck cancer, lung cancer, and 
esophageal cancer. In esophagus squamous cell carcinoma, 9 of 15 (60%) patients had a 
gene copy number between 4 and 20. Similarly, in esophagus adenocarcinoma, 5 of 8 (62%) 
had gene copy number ranging from 4 to 20. In lung cancer, more than three copy numbers 
were found in 6, 9, and 23 percent of adenocarcinoma, small cell lung carcinoma, and 
squamous cell carcinoma, respectively (unpublished data). Nearly 25% of head/neck 
carcinoma also has gene amplification
These observations suggest the ephrin pathway has an oncogenic role and may be a 
potential therapeutic target. 
1.3
Summary of pre-clinical findings of EphB4 in prostate cancer
Expression of EphB4 protein is increased in most prostate cancers and is retained after 
exposure to ADT, but is not commonly expressed in benign prostate tissue. In one study, 66% 
of prostate tumors analyzed had increased EphB4 protein expression, compared to 15% of 
benign prostate tissue [17, 18]. 
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EphB4 is induced by molecular alterations implicated in CRPC development including loss of 
tumor suppressors PTEN and TP53, and activation of the PI3K pathway [17]. The genomic 
signature of MYC activation, PTEN loss, and TP53 loss in prostate cancer has been 
associated with aggressive disease as demonstrated by a shorter time to disease relapse 
after primary treatment, and increased risk of death [23]. Experiments from Dr. Parkash Gill at 
the University of Southern California and Dr. Sarki Abdulkadir at Northwestern University 
showed prostate cancer PTEN knockout mouse models had high EphB4 expression and its 
inhibition with the soluble EphB4-albumin fusion antagonist, sEphB4, led to tumor regression 
in 10 of 10 mice (Figure 1). Additional experiments from Dr. Abdulkadir’s group at 
Northwestern showed that sEphB4 induced tumor cell death and immune infiltration in 
genomically complex transgenic MYC+Pten-Tp53- prostate tumors (Figure 2). Additional 
preclinical studies show that sEphB4 antagonist also causes inhibition of angiogenesis, and 
cytotoxic T cell and NK cell recruitment. EphB4 inhibition also led to inhibition in PC3 prostate 
cancer cell line and C4-2B orthotopic mouse models. These preclinical data support 
therapeutic targeting of the ephrinB2-EphB4 interaction may lead to disease response in 
aggressive prostate cancer. 
Figure 1. Mouse sEphB4-albumin causes regression of PTEN knock out prostate tumor (unpublished data, 
courtesy Dr. Sarki Abdulkadir’s lab at Northwestern University and Dr. Parkash Gill’s lab at University of Southern 
California)
Figure 2. Transgenic mice 
(Myc/Pten/p53) treated with 
20mg/kg sEphB4-MSA or 
vehicle (PBS) a week for 4 
weeks. 
a) Representative images of 
hematoxylin and eosin 
(H&E) and CD3 staining 
from sEphB4-MSA treated or 
PBS treated transgenic 
mice. b) Reduced c-Myc and 
increased cleaved caspase-
3 expression in transgenic 
mice treated with PBS and 
sEphB4-MSA 
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1.4
sEphB4-HSA 
The soluble decoy EphB4 receptor-human serum albumin fusion protein (sEphB4-HSA) is a 
fully human fusion protein with a soluble EphB4 extracellular domain that specifically binds 
ephrin-B2. Thus drug blocks ephrin-B2 binding, bidirectional signaling, and their downstream 
effects on angiogenesis and tumor growth in vitro and in vivo.
In vitro studies demonstrate that sEphB4 binds specifically to EphrinB2 and to EphrinB2-
expressing cells with low nanomolar affinity. sEphB4-HSA blocks EphB4 binding to EphrinB2-
expressing cells, EphrinB2-induced EphB4 phosphorylation, and EphB4 induced EphrinB2 
phosphorylation. As a result, sEphB4-HSA inhibits EphB4-EphrinB2-mediated bidirectional 
signaling, leading to inhibited endothelial invasion, binding to extracellular matrix proteins, and 
tube formation at low nanomolar effective concentration for 50% inhibition (EC50) values. In a 
matrigel plug assay, sEphB4-HSA effectively reduced the angiogenesis induced by VEGF. 
Furthermore, sEphB4-HSA was shown to inhibit cell viability in vitro on a panel of susceptible 
cancer cell lines. In cell line and animal models, sEphB4 produces complete inhibition of PI3K 
signaling measured by phosphoS6 and phosphoAkt. In addition by downregulating PI3K beta, 
sEphB4 markedly reduces androgen receptor expression in a PTEN knock prostate cancer 
model with concurrent major reduction in tumor volume (Gill unpublished data). 
In addition to the aforementioned studies in prostate cancer sEphB4-HSA demonstrated in 
vivo activity in multiple tumor xenograft models, including orthotopic HT29 colon cancer, A549 
lung cancer, and orthotopic PANC265 pancreatic cancer in which it also significantly reduced 
the incidence of tumor metastases. Furthermore, sEphB4-HSA significantly inhibits 
tumorigenesis and/or tumor growth in several spontaneous tumor models including Kras 
mutant oral cavity and skin cancer models. 
sEphB4-HSA was well-tolerated in cynomolgus monkeys when administered as a single i.v. 
injection at dose levels up to 30 mg/kg. In a 5-week multiple and different dose (5 weekly drug 
administration ranging from 0 to 30mg/kg) toxicity study of sEphB4-HSA in cynomolgus 
monkeys, all animals survived until their scheduled necropsy. No anatomical pathology 
findings were present in all animals at the end of the 5-week observation period, nor after the 
recovery period (7-week study). There were no adverse dose-dependent effects observed. 
1.5
Summary of clinical trial findings
In addition to these preclinical studies, the sEphB4-HSA has shown safety and tolerability in a 
first-in human phase I trial of 70 patients with advanced solid tumors. The study included a 
dose escalation phase and dose expansion phase at the maximum tolerated dose (MTD) or 
recommended phase II dose (RP2D). Dose levels tested were 2.5, 5, 10 and 15 mg/kg IV 
infusion weekly and 10, 15, and 20 mg/kg IV infusion every 2 weeks. No dose limiting toxicity 
was observed, except one patient with grade 3 hypertension not responsive to therapy in a 
patient at 20 mg/kg dose requiring dose reduction to 15 mg/kg and one patient with grade 3 
QTC prolongation at 10mg/kg weekly. There were no grade 4 or 5 treatment related adverse 
events. The most common grade 3 toxicities were hypertension (27%), fatigue (16%), nausea 
(4%). Grade 1-2 toxicities included hypertension (48%), fatigue (35%), weight loss (13%), 
nausea (6%), and vomiting (5%). A maximum tolerated dose was not reached. 
Pharmacokinetic studies showed a half-life of 306 hours. Based on these findings, the 
recommended phase II dose was established as 10mg/kg weekly and 20mg/kg every 2 
weeks. Four of 70 patients had a partial or complete response and 50% showed stable 
disease [24]. The median number of cycles received was 2 (range 1-19). Several patients 
have received 4-11 months of therapy indicative of safety when used for prolonged period of 
time. 
Clinical trials are planned to investigate its use as neoadjuvant therapy in genitourinary 
malignancies (NCT02767921) and metastatic bladder cancer in combination with checkpoint 
inhibitor ant-PD1 (NCT02717156).
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1.6
Rationale for the Current Study
A need for improving therapeutic options in mCRPC, extensive preclinical results showing the 
relevance of the EphB4/EphrinB2 pathway in mCRPC along with clinical data demonstrating 
the clinical safety of the soluble decoy EphB4 receptor-human serum albumin fusion protein 
(sEphB4-HSA) provide the foundation for the present proposal of a phase II study to explore 
preliminary efficacy and safety of sEphB4-HSA in patients with progressive mCRPC who have 
previously received a second generation AR targeted therapy (i.e., abiraterone or 
enzalutamide) and chemotherapy (docetaxel or cabazitaxel). 
The patient population was chosen because this group of patients is in need for effective 
therapeutic approaches as they have advanced lethal prostate cancer and limited further 
therapies capable to improve survival. Additionally, based on preclinical models, EphB4 
inhibition maybe more relevant in patients with more aggressive CRPC. 
Patients will be maintained on ADT per standard of care and receive the study drug at the 
recommended phase II dose. Phase I studies showed the safety and tolerability of the 
sEphB4-HSA in patients with advanced cancers but the drug has not been specifically 
evaluated for patients with mCRPC or in combination with ADT.
1.7
Rationale for Exploratory Studies
Our preclinical data showed that EphB4 inhibition by sEphB4-MSA profoundly inhibited tumor 
growth in mouse model of Myc over expression and PTEN loss. In addition, we have also 
found that sEphB4-MSA induces T-Cell infiltration and expression of PD-L1 in tumors 
suggesting a role for immune cell mediated tumor regression. From this evidence, we would 
like to explore the effect of sEphB4-HSA in advanced prostate cancer patients as a single 
treatment or in combination with other agents. The rationale for obtaining archival pathologic 
specimen and peripheral blood to assess molecular features of the patient’s disease is to 
gather correlative data that provides insight into the activity of sEphB4-HSA in this setting if 
response is seen. Results of this study will provide foundational data to further explore 
sEphB4-HSA therapeutic potential in other clinical settings of advanced prostate cancer as 
single agent and in combination with other agents, e.g. if immune cell infiltration associated 
with PD-L1 is seen, this can provide a rationale for combination with immune checkpoint 
therapy.
1.7.1
The role of EphB4 and ephrinB2 in mCRPC and correlation with outcomes 
Mechanistically, sEphB4-HSA acts by binding to Ephrin B2 and preventing it’s binding 
to EphB4. Therefore it is important to evaluate the expression of both binding partners 
and correlate response to therapy if activity of the drug is seen.
1.7.2
The role of molecular biomarkers (PI3K pathway, P53, and MYC expression) and 
their correlation with clinical response of sEphB4.
Our preliminary in vitro and in vivo studies have identified a relationship between 
PTEN/PI3K, Myc and p53 pathway to EphB4 expression and the response to EphB4 
target therapy. Proposed correlation studies are geared towards understanding the 
various genomic alterations that can predict efficacy of sEpHB4. To this end, we will 
perform IHC on available tissue for EPHB4, EFNB2, AR, PTEN, p-AKT, and MYC and 
analyze genomic alterations that are described in the results of molecular analysis 
reports from standard of care tests (i.e., results from standard of care NGS testing/ 
genetic testing/ genomic testing, etc.). We will also utilize cfDNA results to analyze the 
changes in the alteration level at baseline and after treatment.
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2
OBJECTIVES 
2.1
Primary Objective:
2.1.1
To estimate the efficacy of sEphB4-HSA in patients with mCRPC as measured by 
confirmed PSA response rate.
2.2
Secondary Objectives:
2.2.1
The safety and tolerability of sEphB4-HSA in patients with mCRPC according to NCI 
CTCAE v 5.0 (See Appendix II).
2.2.2
To assess the time to PSA progression.
2.2.3
To assess overall response rate in patients with measurable disease using RECIST 1.1 
(soft tissue) and PCWG3 (bone) criteria.
2.2.4
To assess radiological progression free survival (rPFS) using RECIST 1.1 (soft tissue) 
and PCWG3 (bone) criteria.
2.3
Exploratory Objectives: 
2.3.1
To explore molecular changes associated with EphB4 and ephrinB2 expression in 
tumor specimens (primary and/or metastatic tissue). 
2.3.2
To explore association of response with molecular biomarkers including aberrations in 
the PI3K pathway, MYC and TP53.
2.3.3
To assess immune cell infiltration of tumors in archival tissue, if tissue is available.
2.3.4
To assess circulating immune changes associated with treatment.
3
PATIENT ELIGIBILITY
The target population for this study are patients with mCRPC who have progressive disease despite 
castrate levels of testosterone (<50 ng/dL) and have received at least one standard first-line therapy for 
metastatic castrate resistant prostate cancer, which can include therapy with a 2nd generation AR 
targeted therapy (abiraterone or enzalutamide) or chemotherapy (docetaxel or cabazitaxel). This study 
will be a multicenter trial conducted at Northwestern University and will serve as the lead site and 
coordinating center for the study.  Participating sites include University of Chicago and University of 
Southern California. 
A total of 25 evaluable subjects will be needed for this trial. Approximately 4-8 potentially eligible 
patients are seen per month, and it is anticipated that at least 1-2 per month will be accrued (once all 
sites are up and running). 
 
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. Study treatment may not begin until a subject is registered. Please refer to Section 11 for 
complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have a pathologically confirmed diagnosis of prostate 
adenocarcinoma
 
3.1.2
Patients must have metastatic (M1) disease as evidenced by soft tissue and/or 
bony metastases on CT or MRI scan or technetium bone scan. 
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3.1.3
Patients must have castration resistant disease with disease progression despite 
castrate levels of testosterone (testosterone < 50 ng/dL)
3.1.4
Patients must have received and progressed on at least one second generation AR 
targeted therapy for castration resistant disease irrespective of prior chemotherapy. 
No more than 3 prior treatment therapies for castration resistant disease (life 
prolonging) are permitted. Prior therapy can include:

Second generation AR targeted therapy [i.e. abiraterone, enzalutamide, or 
other new antiandrogen (ODM-201, apalutamide)]

Chemotherapy (docetaxel and/or cabazitaxel). 
3.1.5
Documented progressive mCRPC based on at least one of the following criteria: 

PSA progression defined as 25% increase over baseline value with an increase 
in the absolute value of at least 2.0 ng/mL that is confirmed by another PSA 
level with a minimum of a 1 week interval and a minimum PSA of 2.0 ng/mL.

Progression of bidimensionally measurable soft tissue or nodal metastasis 
assessed within one month prior to registration by a CT scan or MRI. (Please 
refer to Section 6.1.2 for definition of measurable disease.)

Progression of bone disease (evaluable disease) (new bone lesion(s)) by bone 
scan.
3.1.6
Serum testosterone < 50 ng/dL. Patients must continue primary ADT with an LHRH 
analogue (agonist or antagonist) if they have not undergone orchiectomy.
3.1.7
Patients must be age ≥ 18 years.
3.1.8
Patients must have an ECOG performance status of 0-2 (See Appendix I Section 
12.1)
3.1.9
Patients must have adequate organ and bone marrow function as defined below 
within   2 weeks prior to registration: 
Absolute Neutrophil Count
≥ 1,000/mcL
Hemoglobin
≥ 9 g/dL*
Bilirubin
≤1.5 x institutional upper limit of 
normal (ULN) except for 
unconjugated hyperbilirubinemia or 
Gilbert’s Syndrome, who can have 
total bilirubin <3.0 mg/dL.
AST/ALT
≤ 3 x ULN (≤ 5 x ULN if liver 
metastases present)
Serum Creatinine
≤ 2.0 X ULN (upper limit of normal) 
or creatinine clearance ≥ 30 
mL/minute (using Cockcroft/Gault 
formula)
Platelet 
>100,000
* Transfusion is allowed as long as patients have not received prior 
transfusion ≤28 days from registration.
3.1.10
Patients must use a condom during treatment and for 3 months after the last dose 
of study treatment when having sexual intercourse. Female partners of male 
subjects should also use a highly effective form of contraception if they are of 
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childbearing potential (See Appendix III Section 12.3). Subjects should not donate 
sperm throughout the study and for 3 months following the last dose of treatment. 
3.1.11
Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study.
3.2
Exclusion Criteria
3.2.1
Patients who have received more than 3 prior treatment therapies (life prolonging) 
for mCRPC are not eligbile.
3.2.2
Patients who have had radiotherapy ≤14 days prior to entering the study are not 
eligible.
Note: Palliative radiation therapy is allowed.
3.2.3
Patients who have had systemic therapy for prostate cancer ≤21 days or 5-half lives 
(whichever is shorter) are not eligible. 
Note: Patients can receive a stable dose of bisphosphonates for bone 
metastases, including zoledronic acid, or denosumab before and during the 
study as deemed appropriate by the treating physician. Patients must continue 
Androgen Deprivation Therapy.
3.2.4
Patients receiving any other investigational agents are not eligible.
3.2.5
Patients with Small cell carcinoma of the prostate are not eligible.
Note: Neuroendocrine differentiation is permitted. If there is doubt about this 
and it is clinically indicated then a biopsy should be obtained to document 
histological differentiation.
3.2.6
Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to sEphB4-HSA are not eligible.
AND
Patients who have had prior exposure to compounds of similar chemical or biologic 
composition to sEphB4-HSA are not eligible.
3.2.7
Patients who have an uncontrolled intercurrent illness including, but not limited to 
any of the following, are not eligible:

Ongoing or active infection requiring systemic treatment

Symptomatic congestive heart failure (New York Heart Association Class III 
or IV congestive heart failure)

Unstable angina pectoris

Serious cardiac arrhythmia
3.2.8
Patients with uncontrolled hypertension (defined as systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 95mmHg) are not eligible. 
Note: Patients with a history of hypertension are allowed provided blood 
pressure is controlled by anti-hypertensive treatment
3.2.9
Patients with Electrocardiogram (ECG) with QT interval (QTc) >480 msec are not 
eligible.
3.2.10
Patients with other malignancy that has progressed or has required active systemic 
treatment in the last 3 years. 
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Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin that has undergone potentially curative therapy or carcinoma in situ 
or non-muscle invasive bladder cancer are not excluded.
3.2.11
Patients with known active CNS metastases and/or carcinomatous meningitis are 
not eligible. 
Note: A scan to confirm the absence of brain metastases is not required. 
Subjects with previously treated brain metastases may participate provided they 
are stable, i.e. without evidence of progression for at least 4 weeks by repeat 
imaging (note that the repeat imaging should be performed during study 
screening), without requirement of steroid treatment for at least 4 weeks prior to 
randomization and with any neurologic symptoms resolved or have returned to 
baseline of prior treatment for brain metastasis
3.2.12
Patients with spinal cord compression are not eligible unless considered to have 
received definitive treatment for this and evidence of stable disease for 28 days. 
3.2.13
Patients who underwent major surgery ≤14 days of starting study treatment or have 
not recovered from effects of surgery are not eligible. 
3.2.14
Patients with a history of significant thromboembolic events, (including recurrent 
DVT, CVAs, or recurrent pulmonary embolism) are not eligible. 
3.2.15
Patients with a history of any of the following are not eligible:

History of noncompliance with other medical therapy for medical conditions 
that could be impacted by study drug-related adverse events.

An illness, condition, or other situation that the treating investigator feels 
would limit compliance with study requirements or would comprise the 
subject’s safety or study endpoints. 
4
TREATMENT PLAN
4.1
Overview
This study plans to enroll two successive cohorts by a Simon two-stage design of 15 and 10 
evaluable patients, for possible total of 25 evaluable patients with progressive mCRPC after 
treatment with at least one first-line therapy for metastatic castration-resistant prostate cancer 
including new AR targeted therapy (i.e. abiraterone, enzalutamide or similar agents) or 
chemotherapy (docetaxel or cabazitaxel or noavel taxane). The second cohort will be 
recruited if the first cohort shows a signal of activity and no signs of unexpected toxicity; see 
section 6.1 for definitions. 

Patients will receive sEphB4-HSA 1000mg IV (60 ±15 min infusion) on day 1  in a 14-
day cycle along with continuation of androgen deprivation therapy. Assessment of 
response to therapy with PSA will be every odd cycle (every 28 days).  Imaging will 
occur at baseline and 2 months after starting therapy; thereafter, imaging will be 
conducted every 3 months. After 1 year, imaging can be done every 4 months for 
patients with stable disease or better. Scans may also be conducted at any time, if 
clinically indicated.  Beginning at Cycle 7, cycle length will be 21 days and patients will 
return for treatment on Day 1 of each cycle.
Note: patients will receive ADT per treating physician’s choice (LHRH 
agonist/antagonist or orchiectomy) as standard therapy.
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
Cell Free DNA (cfDNA) will be collected at baseline and on Day 1 of cycle 5, and at 
disease progression or end of treatment for molecular analysis. We will collect serum 
for cytokine panel analysis (TNFa, IL1beta, IL2, 4, 5, 6, 8, 10, 12, 13) at baseline Day 1 
of cycle 5 prior to drug infusion and at disease progression or end of treatment.
Patients may continue to receive sEphB4-HSA treatment until no longer clinically benefiting 
(PCWG3), unacceptable toxicity, treatment delay ≥4 weeks, or prohibitive illness/change in 
patient’s condition, or patient decides to withdraw from study. Response assessment with 
PSA will occur every odd cycle (28 days).  Imaging will occur at baseline and 2 months after 
starting therapy; thereafter, imaging will be conducted every 3 months. After 1 year, imaging 
can be done every 4 months for patients with stable disease or better. Scans may also be 
conducted at any time, if clinically indicated.  Once off treatment continue follow-up for 4 
weeks or resolution/stabilization of AE. Patients will be followed every 6 months, until 
objective progression, or 1 year.
4.2
Treatment Administration
Table 4-2-1: Premedications *
Premedication
Dose
Route
Schedule
Diphenhydramine*       
25 mg
Treating investigator 
discretion / 
Institutional standards
Administer at least 30 
minutes prior to the 
sEphB4-HSA infusion
Acetaminophen*
650 mg
PO
Administer at least 30 
minutes prior to the 
sEphB4-HSA infusion
* Refer to Section 4.4.3 for (1) changes to the pre-medication regimen for patients who experience 
infusion reactions and (2) management of infusion reactions.
Table 4-2-2: Treatment Administration Summary
Agent
Dose
Route
Schedule
Cycle Length
Supportive 
Therapies*
sEphB4-HSA
 
1000mg
IV over       
60 minutes 
(±15 min)
Cycles 1-6:               
Day 1  of each 
cycle (14 days)
Cycle 7+: 
Day 1 of each 
cycle (21 days)
Cycle 1-6: 
14 days
Cycle 7+: 
(21 days)
Antiemetics
Additional 
medications for 
prophylaxis and 
supportive care 
can be 
administered 
as clinically 
indicated per 
Institutional 
standards.
* Refer to Section 4.4.3 for the management of infusion reactions.
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sEphB4-HSA will be administered intravenously. The dose of sEphB4-HSA will be 1000mg 
intravenously over 60 minutes (±15 min) on day 1 of a 14-day cycle.  Beginning at Cycle 7, 
cycle length will be 21 days and patients will return for treatment on Day 1 of each cycle. 
Premedications include diphenhydramine and acetaminophen as described above in Table 
4-2-1 . Additional medications for prophylaxis and supportive care can be administered as 
clinically indicated per institutional protocol. 
4.3
Toxicity Management & Dose Delays/Modifications
Any patient who receives at least one dose of study therapy will be evaluable for toxicity 
endpoints. Each patient will be assessed for the development of toxicity according to the 
timeframe referenced in the Schedule of Events table (section 5). Toxicity will be assessed 
according to CTCAE v5.0. 

In order to start a new cycle of therapy a patient must have platelets ≥ 
100,000, ANC ≥1,000, and resolution of all treatment-related toxicity (except 
alopecia) to Grade 2 or less or to baseline when baseline was more than 
Grade 2.

A dose can be delayed for up to 7 days for resolution of toxicity. The 
subsequent doses will be delayed so as not to shorten the dosing interval. 

If the dose cannot be given within 7 days of scheduled time it should be 
omitted. Patients who miss 3 consecutive doses will be removed from the 
study. 

Patients will be withdrawn from the study if they fail to recover to CTCAE 5.0 
≤1 or baseline from a drug-related toxicity (except alopecia) ≤4 weeks.

Patients can have a maximum of 2 dose reductions for drug-related toxicity 
beyond which they will be removed from the study. Dose reduction should follow 
the dose levels displayed in the table below. Re-escalation is not permitted. 
Dose modifications
Dose Level
Dose of sEphB4-HSA
Starting Dose
1000mg IV over 60 min every 2 weeks
-1
750 mg IV over 60 min every 2 weeks
-2
500 mg IV over 60 min every 2 weeks
4.3.1
Dose modifications for sEphB4-HSA treatment related toxicity
Toxicity
Grade
sEphB4-HSA
Non-hematologic 
toxicities including 
nausea, vomiting , and 
diarrhea
Grade 1/2
If patients develop intolerable Grade 1 or Grade 2 
toxicities (per patient) then they can undergo a 
dose reduction. For Grade 3/4 toxicities despite 
optimal medical therapy, hold sEphB4-HSA until 
equal or under Grade 1. Resume at one dose level 
reduction.
No routine prophylactic anti-emetic treatment is 
required at the start of study treatment, however, 
patients should receive appropriate anti-emetic 
treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with 
local treatment practice guidelines 
General non-
hematologic toxicities 
excluding nausea, 
Grade 3/4
Any patient who experiences Grade 3 or 4 
unmanageable non-hematologic toxicity (other 
than alopecia) at least possibly related to the study 
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vomiting, and diarrhea
drug will require immediate dose interruption. 
Treatment will be withheld until toxicities have 
resolved to Grade 1 or baseline. After resolution of 
the toxicity, a one dose level reduction will be 
initiated.
Grade 3
Grade 3 AST and/or ALT that does not represent 
at least a two grade increase from baseline – hold 
therapy, recheck weekly. If AST and ALT return to 
baseline grade within 7 days, retreat at same dose 
level. If AST and ALT do not return to baseline 
within 7 days, treatment should be restarted once 
AST and ALT have returned to baseline and dose 
should be reduced by one level.
Grade 3 AST and/or ALT that represents at least a 
two grade increase from baseline or AST/ALT ≥ 
10XULN –hold therapy, recheck weekly, initiate 
retreatment when resolved to baseline with one 
dose level reduction.
AST/ALT
Grade 4
Grade 4 AST and/or ALT– hold therapy, recheck 
weekly, initiate retreatment when resolved to 
baseline with a one level dose reduction.
Any grade AST or ALT that represents a doubling 
from baseline AND that is concurrent with a 
doubling of the total bilirubin- hold therapy, recheck 
weekly, initiate retreatment when resolved to 
baseline grade or grade 1 with one level dose 
reduction.
Grade 2
Patients with grade 2 hypertension as evidenced 
by two or more different measurements that are at 
least one our apart should be initiated on 
antihypertensive therapy per the treating physician. 
BP should be rechecked in one week after 
initiation of antihypertensive therapy; if SBP is still 
>150 and/or DBP is > 100, physician should 
increase the dose of the antihypertensive or add a 
second antihypertensive drug as indicated.
Grade 3
First occurrence, patients may continue on treatment 
while their antihypertensive therapy is optimized. A 
second occurrence of grade 3 hypertension despite 
antihypertensive therapy would require holding 
treatment with sEphB4-HSA until hypertension returns 
to ≤ grade 2 at which point treatment can be resumed 
with one dose reduction.
Hypertension1
Grade 4
Withhold study drug. Optimal management with 
intensive IV support in ICU.
Platelets
Grade 3/4
Hold therapy, recheck weekly, initiate retreatment 
when resolved to Grade 1 or less and restart 
treatment with a one level dose reduction.
Neutropenia
Neutropenic 
fever or Grade 
4 neutropenia
Hold therapy, recheck weekly, initiate retreatment 
when resolved to Grade 1 or less and restart 
treatment with a one level dose reduction.
Anemia
Grade 1 or 
Grade 2 
(Hemoglobin 
(Hb) > 8 g/dl)
Investigate and manage as deemed appropriate by 
the investigator with or without interruption of study 
drug or change in dose, taking into account 
previous history of anemia. Common treatable 
causes of anemia (e.g., iron, vitamin B12 or folate 
deficiencies and hypothyroidism) should be 
excluded. In some cases management of anemia 
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may require blood transfusions.
Grade 3 (Hb < 
8g/dl) or worse
Study treatment should be interrupted for up to 
maximum of 4 weeks to allow for bone marrow 
recovery and the patient should be managed 
appropriately. Study treatment can be restarted at 
the reduced dose level -1 if Hb has recovered to > 
10 g/dl. Any subsequently required anemia related 
interruptions, considered likely to be dose related, 
or coexistent with newly developed neutropenia, 
and or thrombocytopenia, will require a further study 
treatment dose reduction to level -2.
If a patient has been treated for anemia with 
multiple blood transfusions without study treatment 
interruptions and becomes blood transfusion 
dependent as judged by investigator, study 
treatment should be permanently discontinued.
1.
All patients will be educated about the hypertension side effect and instructed to contact the 
study team if their blood pressure remains under poor control between visits. The patients 
may be asked to keep a blood pressure log as per treating physician discretion.
NOTE: Stopping or reducing the dose of study drug can cause a decrease in BP. The 
treating physician should monitor the patient for hypotension and adjust the number and 
dose of antihypertensive medication(s) accordingly.
If the patient experiences a grade 4 allergic or hypersensitivity reaction the drug should 
be permanently discontinued. 
AR targeted therapy will continue per standard of care regardless of sEphB4-HSA 
toxicity.
4.3.2
Toxicities that require discontinuation from protocol therapy
Protocol therapy should be discontinued if a patient experiences:

Any CTC Grade 4 toxicity with the exception of:
o
CTC Grade 4 neutropenia of 5 days or fewer duration
o
CTC Grade 4 nausea/vomiting or diarrhea that resolves to Grade 3 or 
less within 72 hours despite optimal supportive care.
o
CTC Grade 4 laboratory abnormalities that can be readily corrected with 
72 hours and do not result in hospitalization.

CTC Grade 3 thrombocytopenia with hemorrhage

CTC Grade 3 febrile neutropenia

Hy’s Law (AST or ALT >3x ULN with concomitant serum bilirubin >2x ULN and 
no alternate etiology)
4.3.3
Management of Infusion Reaction
Since sEphB4-HSA contains only human protein sequences, it is unlikely to be 
immunogenic and to induce infusion or hypersensitivity reactions. Since sEphB4-HSA 
specifically binds to EphrinB2, this makes it less likely that such a reaction would occur. 
However, if such a reaction were to occur, it might manifest with fever, chills, rigors, 
headache, rash, pruritus, arthralgia, hypo- or hypertension, bronchospasm, or other 
symptoms. Prophylactic premedications will be administered as described in Table 4-2-
1.  Infusion reactions should be graded according to the CTCAE Version 5.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate: 
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For Grade 1 symptoms: (Transient flushing or rash, drug fever < 38C). Remain at 
bedside and monitor subject until recovery from symptoms. 
For Grade 2 symptoms: (Rash, flushing, urticarial, dyspnea, drug fever > 38C) Stop the 
sEphB4-HSA infusion, begin an i.v. infusion of normal saline, and treat the subject with 
25 mg additional diphenhydramine (for total dose of 50 mg, considering prior 
premedication with 25 mg) i.v. (or equivalent) and/or acetaminophen; remain at bedside 
and monitor subject until resolution of symptoms. Corticosteroid therapy (e.g., 
hydrocortisone, PRN, or other Institutional standard) may also be administered as 
appropriate. Additional supportive care may be administered per Institutional standard 
practice. If the infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 
minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
subject closely. If symptoms recur then no further sEphB4-HSA will be administered at 
that visit. The amount of study drug infused must be recorded on the case report form 
(CRF). The following prophylactic premedications are required for future infusions: 
diphenhydramine 50 mg (or equivalent) and acetaminophen 650 mg (or equivalent). 
Corticosteroids (e.g., hydrocortisone or other Institutional standard) are also 
recommended, if clinically indicated. These premedications should be administered at 
least 30 minutes before additional sEphB4-HSA administration. Remain at bedside and 
monitor subject until recovery from symptoms. 
For Grade 3 or Grade 4 symptoms: (grade 3: Symptomatic bronchospasm, with or 
without urticarial, requiring parental medications; allergy related edema/angioedema, 
hypotension OR grade 4: Anaphylaxis as defined as a life-threatening event 
characterized by the rapid onset of airway obstruction including bronchospasm, stridor, 
hoarseness, urticarial and/or hypotension): Immediately discontinue infusion of sEphB4-
HSA. Begin an i.v. infusion of normal saline, and treat the subject as follows: 
Recommend bronchodilators, epinephrine 0.3 mg of a 1:1,000 solution for 
intramuscular administration, or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for 
i.v. administration, and/or diphenhydramine 50 mg i.v. with methylprednisolone 100 mg 
i.v. (or equivalent), as needed. Subject should be monitored until the investigator is 
comfortable that the symptoms will not recur. sEphB4-HSA will be permanently 
discontinued. Investigators should follow their institutional guidelines for the treatment 
of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized 
or generalized pruritus within 1 week after treatment), symptomatic treatment may be 
given (e.g., oral antihistamine, or corticosteroids).
Severe infusion reactions, including fatal reactions, have been observed in mice (but 
not in monkeys). All clinical sites must have immediate access to emergency 
medications and equipment and staff trained in CPR in addition to the ability to rapidly 
transfer patients to an intensive care setting if a patient experiences a severe infusion 
reaction.
4.4
Concomitant Medications/Treatments
Required premedications are described in Table 4-2-1. There are no other known concomitant 
medications or treatments associated or recommended with sEphB4-HSA at this time. 
In the absence of treatment delays due to adverse event(s), concurrent therapy for prostate 
cancer with the exception of ongoing androgen deprivation and anti-resorptive agents such as 
bisphosphonates or denosumab are not permitted. If a patient develops a single symptomatic 
or imminently dangerous metastasis (such as fracture or vertebral compression) then 
intervention with radiation therapy and/or surgery is permitted after discussion with the study 
PI. In this case, study drug would be held during the intervention and recommenced after 
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completion and recovery from any adverse effects. The hold on study drug should not exceed 
4 weeks.
4.5
Duration of Therapy
Treatment may continue until one of the following criteria applies: 

No longer clinically benefiting (PCWG3, symptomatic or objective disease progression by 
RECIST  v1.1 (See Appendix IV))

Intercurrent illness that prevents further administration of treatment  

Unacceptable adverse event(s) as evaluated by the treating physician (see section 4.3) 

Therapy delay for ≥4 weeks  

Patient decides to withdraw from the study or elects to discontinue investigational therapy

General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator  
4.6
Duration of Follow Up
Patients removed from study for progression will return for an End of Treatment (EOT) visit 30 
(±3) days of the last dose of study treatment or prior to initiating new therapy.  Patients 
removed from study for unacceptable treatment-related adverse event(s) will be followed until 
resolution or stabilization of the adverse event. If off treatment for reasons other than disease 
progression, patients will be followed every 6 months, until objective progression or patient 
starts alternative therapy for a maximum of 1 year.
4.7
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients 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:

Patient voluntarily withdraws from treatment (follow-up permitted)

Patient withdraws consent (no follow-up permitted)

Patient is unable to comply with protocol requirements

Patient demonstrates disease progression 

Patient experiences unacceptable toxicity 

Treating physician determines that continuation on the study would not be in the patient’s 
best interest 

Patient develops a second malignancy that requires treatment which would interfere with 
this study

Patient is lost to follow-up (LTF) 
4.8
 Patient Replacement
Any patient who signs consent and is registered for the trial but does not receive study 
treatment may be replaced.
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5
STUDY PROCEDURES
On Treatment  (1 Cycle = 14 Days)
Off Treatment
Screening 
(≤1 month 
unless 
otherwise 
indicated) 
17,3
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7+13
Time Period
Baseline
Week 1
Day 1 
Week 3
Day 1 
Week 5
Day 1 
Week 7
Day 1 
Week 9
Day 1 
Week 11
Day 1 
Week 13
Day 1 
End of 
Treatment14
Follow
-up15
Assessment or Activity
Informed Consent
X
Medical history16 
X16
X16
Physical exam1
X
X
X
X
X
X
X
X
ECOG status
X
X
X
X
X
X
X
X
Toxicity assessment
X
X
X
X
X
X
X
Review Concomitant Medications
X
X
X
X
X
Tumor Imaging2
X
X2,12
X
CBC + diff, chemistry, liver 
enzymes*,3, 4
X
X
X
X
X
X
X
X
PSA*,5
X
X
X
X
X
EKG*,6
X
X
As clinically indicated
As Clinically 
Indicated
Research blood7 
X
X
X
 Archival tissue sample8, 9, 10
X
X
sEphB4-HSA administration11 
X
X
X
X
X
X
Survival Status
See Table 
Below
X
*Can be competed ±3 days of drug administration
1.
Includes vital signs (pulse, blood pressure) and height (baseline only) and weight.
2.
Bone scan, CXR or CT of chest, CT or MRI or abdomen and pelvis; with IV contrast if renal function adequate; the same modality used at baseline 
should be used throughout as clinically indicated.  Imaging will occur at baseline and 2 months (± 7 days) after starting therapy; thereafter, imaging will 
be conducted every 3 months (± 7 days). After 1 year, imaging can be done every 4 months (± 7 days) for patients with stable disease or better. Scans 
may also be conducted at any time, if clinically indicated.
3.
Study labs include: CBC with diff, alkaline phosphatase, albumin, total bilirubin, BUN, creatinine, calcium, glucose, AST, ALT, and electrolytes. These 
study safety labs are to be conducted within ≤2 weeks prior to registration. 
4.
Testosterone level only at baseline. 
5.
Assessment of response to therapy with PSA will occur on day 1 of odd cycles, 
6.
Required for all patients at baseline and C3D1. Then only as clinically indicated thereafter.
7.
Blood will be collected at baseline, cycle 5 day 1, and at end of treatment for additional molecular analysis (see section 9).

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8.
Permission to obtain archival tissue samples of primary lesion and metastatic lesion sites will be obtained at baseline. The samples themselves will be 
collected only if available and only when requested by the Principal Investigator or Principal Investigator’s designee; they may be collected at any time 
during the study, per PI request. Refer to the lab manual for details. 
9.
If there is concern about transformation to small cell cancer histology then a standard of care biopsy may be appropriate given that this is an 
exclusion criteria for this trial. 
10. If tumor tissue is biopsied or resected as part of standard medical care or assessment from the time of study enrollment until progression then 
archival tissue from this biopsy/resection may be used for assay of the markers defined within the protocol to document molecular pathway 
characteristics and immune cell infiltration at that point to correlate with whether the cancer is responding, stable or progressing.  
11. Patients will receive sEphB4-HSA 1000mg IV (60min infusion) on day 1 of each cycle along with continuation of androgen deprivation therapy.  Refer 
to Table 4-2-1 for required premedication regimens. 
12. Imaging must be completed and reviewed within 6 days (whenever feasible) prior to receiving treatment.
13. Please see Table Below. Beginning at Cycle 7, cycle length will be 21 days and patients will return for treatment on Day 1 of each cycle.  
14. Patients will return for an End of Treatment (EOT) visit 30 (±3) days of the last dose of study treatment or prior to start of new treatment. 
15. If off treatment for reasons other than disease progression, patients will be followed every 6 months, until objective progression or patient starts 
alternative therapy for a maximum of 1 year.
16. If patient has had molecular testing (i.e., NGS testing, genetic testing, genomic testing, etc.) performed as standard of care prior to study entry or at 
any time during study participation, collect a copy of the results report for correlative analyses. Refer to Section 9 for details.
17. Screening/baseline assessments are to be conducted within 1 month prior to registration unless otherwise indicated.

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Study Calendar Beginning at Cycle 7
On Treatment (1 Cycle  = 21 Days)
Off Treatment
Cycle 7
Cycle 8
Cycle 9
Cycle 10
Cycle 11
Cycle 12+
Time Period
Week 13
Day 1 
Week 16
Day 1 
Week 19
Day 1 
Week 22
Day 1 
Week 25
Day 1
Week 28
Day 1
End of 
Treatment14
Follow-
up15
Assessment or Activity
Informed Consent
Medical history16 
X16
Physical exam1
X
X
X
X
X
X
X
ECOG status
X
X
X
X
X
X
X
Toxicity assessment
X
X
X
X
X
X
X
Review Concomitant Medications
X
X
X
X
X
X
X
Tumor Imaging2
X12, 13
X
CBC + diff, chemistry, liver enzymes*,3, 4
X
X
X
X
X
X
X
PSA*,5
X
X
X
X
X
X
X
EKG*,6
As clinically indicated
Research blood7 
X
 Archival tissue sample8, 9, 10
X
sEphB4-HSA administration11 
X
X
X
X
X
X
Survival Status
X
*Can be competed ±3 days of drug administration
1.
Includes vital signs (pulse, blood pressure) and height (baseline only) and weight.
2.
Bone scan, CXR or CT of chest, CT or MRI or abdomen and pelvis; with IV contrast if renal function adequate; the same modality used at baseline 
should be used throughout as clinically indicated.
3.
Study labs include: CBC with diff, alkaline phosphatase, albumin, total bilirubin, BUN, creatinine, calcium, glucose, AST, ALT, and electrolytes. 
4.
Testosterone level only at baseline. 
5.
Assessment of response to therapy with PSA will occur on day 1 of each cycle, 
6.
Required for all patients at baseline and C3D1. Then only as clinically indicated thereafter.
7.
Blood will be collected at baseline, cycle 5 day 1, and at end of treatment for additional molecular analysis (see section 9).
8.
Permission to obtain archival tissue samples of primary lesion and metastatic lesion sites will be obtained at baseline. The samples themselves will be 
collected only if available and only when requested by the Principal Investigator or Principal Investigator’s designee; they may be collected at any time 
during the study, per PI request. Refer to the lab manual for details. 
9.
If there is concern about transformation to small cell cancer histology then a standard of care biopsy may be appropriate given that this is an 
exclusion criteria for this trial. 
10. If tumor tissue is biopsied or resected as part of standard medical care or assessment from the time of study enrollment until progression then 
archival tissue from this biopsy/resection may be used for assay of the markers defined within the protocol to document molecular pathway 
characteristics and immune cell infiltration at that point to correlate with whether the cancer is responding, stable or progressing.  
11. Patients will receive sEphB4-HSA 1000mg IV (60min infusion) on day 1 of each cycle along with continuation of androgen deprivation therapy.  Refer 
to Table 4-2-1 for required premedication regimens. 
12. Imaging must be completed and reviewed prior to receiving treatment.

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13. Imaging will occur at baseline and 2 months (± 7 days) after starting therapy; thereafter, imaging will be conducted every 3 months (± 7 days). After 1 
year, imaging can be done every 4 months (± 7 days) for patients with stable disease or better. Scans may also be conducted at any time, if clinically 
indicated.   
14. Patients will return for an End of Treatment (EOT) visit 30 (±3) days of the last dose of study treatment or prior to start of new treatment. 
If off treatment for reasons other than disease progression, patients will be followed every 6 months, until objective progression or patient starts 
alternative therapy for a maximum of 1 year.
15. If off treatment for reasons other than disease progression, patients will be followed every 6 months, until objective progression or patient starts 
alternative therapy for a maximum of 1 year.
16. If patient has had molecular testing (i.e., NGS testing, genetic testing, genomic testing, etc.) performed as standard of care prior to study entry or at 
any time during study participation, collect a copy of the results report for correlative analyses. Refer to Section 9 for details.

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6
ENDPOINT ASSESSMENT
6.1
Definitions
6.1.1
Evaluable patients
Evaluable for primary endpoint of PSA response. All patients who received at least 1 
dose of the study drug and who also had a followup PSA test conducted prior to 
initiating subsequent therapy will be evaluable for PSA response. 
Evaluable for toxicity. All patients who received at least 1 dose of the study drug will be 
evaluable for toxicity.  
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline will be considered evaluable for objective response. These patients 
will have their response classified according to the definitions stated below.
Evaluable Non-Target Disease Response. Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease will 
be considered evaluable for non-target disease. The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions.
6.1.2
Disease Parameters by RECIST V1.1
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 by 
chest x-ray, as >10 mm with CT scan, or >10 mm with CT scan, MRI, or calipers by 
clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters).
Note: Tumor lesions that are situated in a previously irradiated area should not 
be considered measurable unless they have demonstrated progression. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm 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 <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis of skin or lung, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts
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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 non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions.
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. A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease.
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions 
and should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each 
should be noted throughout follow-up.
6.1.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 6 weeks before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam.
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. 
for body scans).
As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up should be the same 
as was used at baseline and the lesions should be measured/assessed on the same 
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pulse sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body 
scans should be performed with breath-hold scanning techniques, if possible.
6.1.4
Methods of Evaluation of Bone disease:
Bone disease will be evaluated using technetium Radionuclide bone scan and 
PCWG3 using PCCTC bone scan forms.  
6.1.5
PSA response criteria:
These definitions are intended to characterize the PSA changes on study for the 
purpose of reporting of results.
Complete Response (CR): Undetectable PSA (<0.2 ng/ml) that is confirmed by 
another PSA level at no less than 4 weeks interval (+/- 3 days).
Partial Response (PR): Decrease in PSA value by > 50% that is confirmed by 
another PSA level at no less than 4 weeks interval (+/- 3 days).
Stabilization (SD): Patients who do not meet the criteria for PR or PD for at least 90 days 
on study will be considered stable
Progression (PD): 25% increase over baseline or nadir whichever is lower and an 
increase in the absolute value of PSA level by 2 ng/ml that is confirmed by another 
PSA level at no less than 4 weeks interval.
6.1.6
Evaluation of target lesions by RECIST v1.1
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.
Partial Response (PR): At least a 30% decrease in the sum of the
diameters of target lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the
diameters of target lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR
nor sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.
6.1.7
Evaluation of Non-Target Lesions by RECIST v1.1 (excluding bone lesions, 
which will be assessed as below)
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological in 
size (<10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits.
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Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not 
normally trump target lesion status. It must be representative of overall disease 
status change, not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal Investigator).
6.1.8
Evaluation of bone disease based on Radionuclide bone scans by PCWG3:
Changes in intensity will not be used as an outcome measure.
Stable or Improved: A stable or improved classification requires that no new lesions 
appear on radionuclide bone scan or that new pain has not developed in an area that 
was previously visualized.
Progression (Non-Response): Appearance of two or more new skeletal lesions that is 
confirmed on a repeat scan.  An increase in the size or intensity of known skeletal 
lesions will not be considered progression.
6.1.9
Evaluation of best overall response by RECIST V1.1 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., 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- CR/Non- 
PD/not evaluated
No
PR
SD
Non- CR/Non- 
PD/not evaluated
No
SD
PD
Any
PD
Any
PD***
PD
Any
Any
Yes
PD
no prior SD, PR or CR
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*    See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
*** In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression.
Note: Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration.” Every effort should be made to document 
the objective progression even after discontinuation of treatment.
For Patients with Non -Measurable Disease (i.e., Non Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-
PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised
6.2
Assessment of primary endpoint
The assessment of the primary endpoint of confirmed PSA response rate is defined as the 
proportion of subjects who received at least 1 dose of the study drug achieving a post-
treatment PSA partial response or complete response as defined by PSA response criteria 
in section 6.1.5 
6.3
Assessment of secondary endpoints
6.3.1
The safety and tolerability of sEphB4-HSA in patients with mCRPC will be assessed 
according to NCI CTCAE v 5.0 and reported by the toxicity, severity, and attribution 
will be recorded for each cycle.
6.3.2
The time to PSA progression will be assessed by calculating the interval from 
administration of the first dose of drug on cycle 1 day 1 to PSA progression. PSA 
progression is defined by the criteria in section 6.1.5 PSA will be assessed every odd 
cycle.
6.3.3
The overall response rate will be the proportion of patients with measurable disease 
who received at least 1 dose of the study drug and as their best response achieved a 
partial or complete response (responder). A subject will be classified as a responder 
if the RECIST 1.1 criteria for a CR or PR are satisfied (see 10.1.6 and10.1.7) as well 
as the absence of confirmed progression on bone scan assessed by PCWG3 (see 
10.1.8) at any time up to and including the defined analysis cut-off point. Disease 
evaluation will be assessed by imaging at baseline and 2 months after starting 
therapy; thereafter, imaging will be conducted every 3 months. After 1 year, imaging 
can be done every 4 months for patients with stable disease or better. Scans may 
also be conducted at any time, if clinically indicated.   
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6.3.4
The time to radiologic progression (rPFS) will be assessed by calculating the interval 
from administration of the first dose of drug on cycle 1 day 1 to the time to radiologic 
progression by RECIST 1.1 or PCWG3 bone criteria (10.1.6-108) or death from any 
cause. Imaging will occur at baseline and 2 months after starting therapy; thereafter, 
imaging will be conducted every 3 months. After 1 year, imaging can be done every 4 
months for patients with stable disease or better. Scans may also be conducted at 
any time, if clinically indicated. 
6.4
Exploratory Endpoints
6.4.1
EphB4 and ephrinB2 expression will be assessed by IHC staining of primary and/or 
metastatic site (recent archival specimen or new biopsy). EphB4 and other biomarker 
abnormalities will be assessed by analyzing genomic alterations that are described in 
the results of molecular analysis reports that are obtained from standard of care tests 
(i.e., results from standard of care NGS testing/ genetic testing/ genomic testing, etc.)
6.4.2
Analysis of cfDNA for abnormalities in PI3K pathway, MYC or TP53. 
6.4.3
IHC for CD3, CD4, CD8, and NK cell markers to characterize the immune infiltrate in 
tumor specimen. 
7
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The level of risk 
attributed to this study requires High Risk Monitoring, as outlined in the DSMP. In addition, the study 
will abide by all safety reporting regulations, as set forth in the Code of Federal Regulations.  
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial (see Section 5 for time points). In addition, certain 
adverse events must be reported in an expedited manner to allow for optimal monitoring 
and patient safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, will 
be followed until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 

any abnormal laboratory values have returned to baseline; 

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.
7.2
Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention. 
Recording of AEs should be done in a concise manner using standard, acceptable 
medical terms. In general, AEs are not procedures or measurements, but should 
reflect the reason for the procedure or the diagnosis based on the abnormal 
measurement. Preexisting conditions that worsen in severity or frequency during the 
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study should also be recorded (a preexisting condition that does not worsen is not an 
AE). Further, a procedure or surgery is not an AE; rather, the event leading to the 
procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome should be 
recorded as the AE whenever possible.  However, a complete description of the 
signs, symptoms and investigations which led to the diagnosis should be provided. 
For example, if clinically significant elevations of liver function tests are known to be 
secondary to hepatitis, “hepatitis” and not “elevated liver function tests” should be 
recorded. If the cause is not known, the abnormal test or finding should be recorded 
as an AE, using appropriate medical terminology (e/g/ thrombocytopenia, peripheral 
edema, QT prolongation).
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The CTCAE v 5.0 is 
available at  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm
If no CTCAE grading is available, the severity of an AE is graded as follows:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.  
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living*.
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self 
care activities of daily living**. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE
*Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.  
**Self care activities of daily living refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed consent, 
through 30 days after the last administration of study drug, must be reported upon 
discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more 
severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
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Any event that does not meet the above criteria, but that in the judgment 
of the investigator jeopardizes the patient, may be considered for 
reporting as a serious adverse event. The event may require medical or 
surgical intervention to prevent one of the outcomes listed in the 
definition of “Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

is unexpected (in terms of nature, severity, or frequency) given the 
procedures described in the research protocol documents (e.g., the IRB-
approved research protocol and informed consent document) and the 
characteristics of the human subject population being studied

is related or possibly related to participation in the research ("possibly 
related" means there is a reasonable possibility that the incident, experience, 
or outcome may have been caused by the procedures involved in the 
research); and 

suggests that the research places human subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized, even if no harm has actually occurred.
7.3
Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF. Routine AEs will be reviewed by the Data and Safety Monitoring Committee 
(DSMC) according to the study’s phase and risk level, as outlined in the DSMP. 
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 5.0.
2)
Grade the adverse event using the NCI CTCAE v 5.0.
3)
Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
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7.3.3.1
Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned QAM within 24 hours of becoming 
aware of the event. Completion of the NU CTO SAE Form, provided as a 
separate document, is required.
The completed form should assess whether or not the event qualifies as a 
UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)

Country of incidence
All SAEs will be reported to, and reviewed by, the DMC per the DSMP.
7.3.3.2
Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow their local 
IRB guidelines for reporting to their local IRBs.

Any death of an NU subject that is unanticipated in nature and at least 
possibly related to study participation will be promptly reported to the NU 
IRB within 24 hours of notification. 

Any death of a non-NU subject that is unanticipated and at least possibly 
related and any other UPIRSOs will be reported to Northwestern University 
and to the NU IRB within 5 working days of notification.

Information pertaining to an NU subject that fits into any of the categories 
listed on the Reportable New Information page will be reported to the NU 
IRB within 5 business days of knowledge or notification
7.3.3.3
Reporting to VasGene Therapeutics, Inc
SAEs will be reported within 24 hours/1 business day to VasGene 
Therapeutics by e-mail (linda@vasgene.com) using the NU CTO SAE form.
7.3.3.4
Reporting to the FDA
The FDA will be notified within 7 calendar days of any SAE that is associated 
with study treatment, is unexpected, and is fatal or life-threatening.
The FDA will be notified within 15 calendar days of any SAE that is associated 
with the study treatment, unexpected, and serious but not fatal or life-
threatening. This includes any previous SAEs that were not initially deemed 
reportable, but are later determined to meet the criteria for reporting (i.e. by the 
DSMC).
All other SAEs will be reported on an annual basis as part of the annual FDA 
report.
8
DRUG INFORMATION
8.1
sEphB4-HSA
8.1.1
Other names 
None
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8.1.2
Classification - type of agent
sEphB4-HSA is a fully human recombinant protein consisting of the extracellular 
domain (aa 1 to 522) of EphB4 receptor at the N-terminus and human albumin 
(aa 1 to 585) at the C-terminus. sEphB4-HSA specifically binds to EphrinB2, a 
trans-membrane ligand and member of Ephrin ligand family. EphrinB2 is the only 
ligand for EphB4 receptor.
8.1.3
Mode of action
sEphB4-HSA binds to EphrinB2 with high affinity (5-10nM) and blocks interaction with 
cell surface EphB receptors, thus blocking forward and reverse signaling.
8.1.4
Storage and stability
The Drug Product contains sEphB4-HSA at 25 mg/mL in 10 mM L-Histidine, 150 mM 
Sodium Chloride, and 10% Sucrose, pH 7.0.
sEphB4-HSA vials must be stored at a temperature 2-8°C and should be protected 
from light. Recommended safety measures for preparation and handling of sEphB4-
HSA using standard practice. Once diluted in an IV bag for administration, sEphB4-
HSA can be stored for up to 12 hours at room temperature/under room light and 24 
hours at 2° to 8°C in the refrigerator. Care must be taken to ensure sterility of the 
prepared solution as the product does not contain any antimicrobial preservative or 
bacteriostatic agent.
8.1.5
Protocol dose specifics
sEphB4-HSA will be given as 1000mg IV infusion over 60 minutes (±15 minutes) 
every 2 weeks on day 1 (± 3) of each cycle during Cycles 1-6 (1 cycle =14 days).  
Beginning at Cycle 7, patients will receive sEphB4-HSA every 3 weeks on Day 1 of 
each cycle (1 cycle = 21 days).
Refer to Table 4-2-1 for required premedication regimens. 
8.1.6
Preparation

Each vial contains 250 mg of drug in a 10 mL volume (vial concentration 25 
mg/mL). 

The product is a clear, colorless to light straw yellow sterile solution in 10 mL 
glass vials. 

Allow the appropriate number of vials of sEphB4-HSA to stand at room 
temperature for approximately 15 minutes before preparation. 

Ensure that the sEphB4-HSA solution is a colorless, clear to slightly opalescent 
solution, essentially free of particles on visual inspection. 

Aseptically withdraw the required volume of sEphB4-HSA solution into a syringe, 
and dispense into an IV bag. (If multiple vials are needed for a subject, it is 
important to use a separate sterile syringe and needle for each vial to prevent 
problems such as dulling of needle tip, stopper coring, repeated friction of 
plunger against syringe barrel wall and so on). 

The necessary dose should be diluted in appropriate size bag of 0.9% sodium 
chloride to a total volume of 200 mL. EVA, PVC-free or PVC bags can be used 
for drug preparation. 

Mix by GENTLY inverting several times. DO NOT shake. 

Visually inspect the final solution. If the infusion is not clear or the contents 
appear to contain precipitate, the solution should be discarded and documented 
on the Drug Accountability Log. 

Administer over 60 (±15) minutes via 0.2 μm in-line filter.

Care must be taken to ensure sterility of the prepared solution as the product 
does not contain any antimicrobial preservative or bacteriostatic agent.
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8.1.7
Route of administration for this study
Administered IV via peripheral or central line. Administer with 0.2 μm in-line filter.  
8.1.8
Incompatibilities
No known incompatibilities, sEphB4-HSA should be given through a dedicated 
intravenous line. Do not co-administer other medications at the same line.
8.1.9
Availability & Supply 
sEphB4-HSA will be shipped to each site from VasGene Therapeutics, Inc. Additional 
supplies can be ordered using the drug supply form provided VasGene Therapeutics, 
Inc.  The product is a clear, colorless to light straw yellow sterile solution in 10 ml 
glass vials. Each vial contains 250 mg of drug in a 10 mL volume (vial concentration 
25 mg/ml). The vial is closed with an appropriately sized stopper and seal.
8.1.10
Side effects
Please refer to most recent for IB for full list of Reported Adverse Events.
8.1.11
Nursing implications
Attach the IV bag containing the sEphB4-HSA solution to administration set (tubing) 
with 0.2 μm in-line filter, and infusion pump. The infusion rate of the infusion pump 
should be adjusted to allow for a total infusion time of 60 minutes (±15 minutes). At 
the end of the infusion period, flush the line with a sufficient quantity of normal saline. 
Do not administer study drug as an i.v. push or bolus injection.
8.1.12
Return and Retention of Study Drug
Any partially used and unused drug can be destroyed per the institution’s drug 
destruction policy 
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9
CORRELATIVES/SPECIAL STUDIES 
9.1
Description of Correlative studies:
9.1.1
The role of EpHB4 in driving mCRPC
Abundant evidence from human and transgenic mouse studies indicate that 
alterations in key cancer genes, including MYC, an oncogene and PTEN, a tumor 
suppressor and negative regulator of PI3K activity can conspire to lead to aggressive 
prostate cancer [23]. EphB4 supports cMYC expression at transcriptional level in 
Correlative Samples - Details for Lab Manual 
Correlative study 
Recent archival tumor tissue (primary and 
metastatic) if available.
Blood 
Mandatory or Optional
Optional
Mandatory
Timing (+/- windows)
When requested by the Principal 
Investigator or Principal Investigator’s 
designee; Samples may be collected at 
any time during the study per PI request.
Baseline, cycle 5 day 1, EOT
Volume Needed (blood 
only)
--
10ml
2ml
Tube type needed (blood 
only)
--
10ml EDTA tubes
Draw blood in a plain, 
red-top tube(s), serum 
gel tube is acceptable. 
Tissue thickness and/or # 
slides (tissue only)
Up to 12 slides at 5µm thickness
--
Processing center (e.g. 
PCF-CTU)
Each Institution
Each Institution
Spin down within 2 
hours and send 1 mL of 
serum frozen in a 
plastic vial.
Sample 
handling/processing 
instructions
Each institution will send samples to NU 
PCF-CTU
Each institution will 
send samples to NU 
PCF-CTU
Each institution will 
send samples to NU 
PCF-CTU
Contact person
CTUtissuerequests@northwestern.edu
PCF-
CTU@northwestern.edu
PCF-
CTU@northwestern.edu
Shipping/delivery info 
PCF-CTU 
Samples must be shipped overnight 
Monday-Thursday only.
PCF-CTU 
Samples must be 
shipped overnight 
Monday-Thursday only.
PCF-CTU 
Samples must be 
shipped overnight 
Monday-Thursday only.
Storage needs
For long term, sections will be stored at 
4°C
For long term, samples 
will be stored at -80°C  
at NU PCF-CTU
For long term, samples 
will be stored at -80°C
Analysis center
Abdulkadir Lab
 
Samples will be stored 
for future analysis at 
Northwestern 
University.
Abdulkadir Lab
Assay methodology
IHC
Note: Tissue for IHC will be second 
priority.
Sequencing
Cytokine Panel
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colon cancer [25]. Further, kinomic analyses of EphB4 mutations in lung cancer 
revealed the involvement of PTEN or TP53 loss, and activation of EGFR or IGF1R 
pathways [26]. EphB4 can promote tumorigenesis by engaging multiple signaling 
pathways, including the PI3 kinase/AKT pathway [27]. We are particularly interested 
in determining if sEphB4-HSA treatment modulates PI3K/AKT pathways in Myc 
driven tumorigenesis. For this, we will evaluate the expression of MYC, PI3K and 
downstream mediators pS6K. 
In addition to PI3K pathways, preliminary studies from Dr. Abdulkadir and Dr. Gill’s 
laboratories show that the expression of EphB4 level is retained after Androgen 
Deprivation Therapy (ADT), indicating that it can be a target in cancers after ADT. 
We also want to explore if sEphB4-HSA cooperates with enzalutamide or 
abiraterone. There is an interesting relationship between the PI3K and AR pathways 
in castration-resistant prostate cancer with therapeutic implications. Combining AR 
inhibition with PI3K inhibition may be an effective strategy for treating Pten-null 
CRPC [28]. As shown in the preliminary results, sEphB4 treatment inhibits that PI3K 
pathway, thereby providing a rationale or combining sEphB4 with AR pathway 
inhibition. We will evaluate the expression of AR in primary and metastatic tissue of 
patient and correlate the status of AR as a predictive biomarker for response to 
sEphB4-HSA treatment. 
Mechanistically, sEphB4-HSA acts by binding to Ephrin B2 and preventing it’s 
binding to EphB4. Given the cooperation between Ephrin B2 expressing endothelial 
cells and EphB4 expressing tumor cells [29], it is important to investigate the 
expression of both molecules in this treatment setting. To this end, we will evaluate 
the expression of EphB4 and Ephrin B2 in the tumor microenvironment of patient 
tissue and correlate to treatment response. 
We also aim to understand the impact of sEphB4-HSA treatment on the tumor 
microenvironment in general and immune cell infiltration to the metastatic tumor site 
in particular. Ephrin B2, the binding partner of sEphB4-HSA and EphB4 receptor 
plays a prominent role in suppression of activated T cells [30]. Our preliminary in vivo 
studies showed the increase of CD3 cells in transgenic mice (Pten-,Myc+ P53-) 
treated with sEphB4-MSA. Therefore, it is worthwhile to study tumor-infiltrating 
lymphocytes in tumor tissues from baseline evaluation and response evaluation time 
points. Specifically, we will investigate the expression of CD4+ Helper T cells and 
CD8+ Cytotoxic T cells, and CD31+ Endothelial cells.
9.1.2
EphB4 activation and other associated genes as a biomarker for response
EphB4 is known to be upregulated in most cancer tissues. Furthermore, preclinical 
evidence from mouse model of aggressive prostate cancer with Myc amplification 
and PTEN showed significant tumor regression following EphB4 targeted therapy. 
Therefore it is of high significance to identify genomic alterations in EphB4 and other 
associated genes like Myc, p53, PI3k and AR to predict clinical response. We will 
analyze standard of care genetic/genomic/NGS testing reports to identify genetic 
alterations including MYC, AR, P53 and other most commonly mutated cancer driver 
genes. We will also analyze through immunohistochemistry the baseline level of 
EphB4 and Ephrin B2 and the molecular drivers of mCRPC mentioned in 9.1.1, their 
co activation with EphB4 and contribution to development of mCRPC [18].
9.1.3
The landscape of genomic alterations in the course of sEphB4 treatment
CfDNA has emerged as an efficient non-invasive biomarker that not only correlates to 
cancer stage and response to therapy but also identifies somatic mutations acquired 
with therapy predicting pathways involved in drug resistance [31]. cfDNA will be 
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isolated from the blood samples and stored for future analysis and analyzed by NGS 
testing
9.2
Sample Collection Guidelines
From each patient, specimens will be collected as below:
a.
If available, archival tissue of primary tumor and metastic tumor will be obtained.
b.
Blood for cfDNA (pre-treatment, Cycle 3 Day 1 and at clinical progression or when 
off study, whichever is first)
Please refer to  Lab Manual for instructions on sample collection.
9.3
Sample Processing, Storage, and Shipment
See the Lab Manual for instructions on sample processing, storage and shipment.
9.4
Assay Methodology
9.4.1
Immunohistochemistry:
For metastatic and primary tumor samples we will follow the standard protocol for 
immunohistochemistry to perform qualitative and quantitative measurement of 
EphB4, EphrinB2, PI3K-AKT pathway, MYC, PTEN pathway, AR, and for markers of 
Tumor Infiltrating lymphocytes and endothelial cells For immune cell staining, the 
pathologist will assign scores of 0, 1+, 2+ or 3+ based on staining intensity and 
percent positive cells per unit area of section
9.4.2
Next Generation Sequencing
cfDNA samples will be analyzed by NGS assays at Northwestern University. 
9.5
Specimen Banking
Research samples will be stored at the Abdulkadir Lab or Northwestern University 
Pathology Core Facility until the material has been exhausted or the repository is 
discontinued after the trial is completed. If the repository is permanently closed, all stored 
sample material will be destroyed. Samples may be maintained beyond the death of the 
participant.
10
STATISTICAL CONSIDERATIONS
This is a single-arm study evaluating the efficacy, safety, and tolerability of sEphB4-HSA in patients 
with mCRPC. Analysis populations are defined below. 
10.1
Sample size and Statistical and data analysis plan for the primary objective.
To estimate preliminary efficacy we will assess PSA response rate (PR and CR) with a 
Simon two stage minimax design. We assume the undesirable overall response rate 
(null hypothesis) to be approximately 10% or less, and the alternate hypothesis suggesting 
success to be approximately 30% or more. Fifteen patients will be added in the first stage. 
If 2 or more respond, then an additional 10 patients will be added for a total of 25 evaluable 
patients. If not, we will stop the study after the first stage.  The study will be assessed by 
the DSMC for excess toxicity at this point in time and stopped if DSMC finds excessive 
toxicity. If the second stage is completed, five or fewer successes will suggest failure and 
six or more responses a success of the entire study. This design has a Type I error rate of 
less than 5% and 80% or greater power. It has a 55% chance of stopping early after the 
first stage if the true response rate is 10% or less, and a total expected long run average 
sample size of n=19.5. See below, using Pass 11 software. 
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Two-Stage Clinical Trials Sample Size
Possible Designs For P0=0.100, P1=0.300, Alpha=0.050, Beta=0.200
                                                                                                                        Constraints       
N1       R1           PET          N        R        Ave N        Alpha          Beta                    Satisfied       
25         5         0.000         25        5         25.00         0.033         0.193               Single Stage       
15        1       0.549        25        5       19.51       0.033       0.198                  Minimax       
10         1         0.736         29        5         15.01         0.047         0.195                    Optimum       
References
Simon, Richard. 'Optimal Two-Stage Designs for Phase II Clinical Trials', Controlled Clinical Trials, 
1989, Volume 10, pages 1-10.
Report Definitions
N1 is the sample size in the first stage.
R1 is the drug rejection number in the first stage.
PET is the probability of early termination of the study.
N is the combined sample size of both stages.
R is the combined drug rejection number after both stages.
Ave N is the average sample size if this design is repeated many times.
Alpha is the probability of rejecting that P<=P0 when this is true.
Beta is the probability of rejecting that P>=P1 when this is true.
P0 is the response proportion of a poor drug.
P1 is the response proportion of a good drug.
PSA response rate will be reported with two-sided 80% exact binomial confidence interval 
(corresponding to the one-sided α=0.10). 
10.2
Analysis of secondary and exploratory objectives
To estimate the distributions of time to PSA progression and rPFS (defined in Section 6.3), 
we will use Kaplan Meier methods, and estimate the median with two-sided 90% CI.
 
The estimated overall response rate in patients with measurable disease (Section 6.1.1) 
will be reported with two-sided 90% exact binomial CI. 
For each patient within the population evaluable for toxicity (Section 6.1.1), recorded AE data 
over time will consolidated as the maximum grade observed of each AE type. All reported 
AE types will be tabulated by maximum grade using frequencies and percentages. Data on 
type, timing, frequency and attribution of AEs will also be summarized.
To explore if PSA response is associated with expression of EphB4 and ephrinB2 in archival 
metastatic and primary tumor CRPC specimens, and/or with aberrations in the PI3K pathway, 
P53, MYC. Marker values will be summarized according to PSA response status. Summaries 
will be descriptive and graphical; hypothesis testing is not planned.
10.3
Accrual
This multi-site trial will accrue patients at University of Chicago, University of Southern 
California and Northwestern University.   Four-eight potentially eligible patients are seen 
per month at participating sites. Accordingly, we plan to enroll 1-2 patients per month. We 
expect it will take 18 months to accrue our study population. 
11
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
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In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by VasGene 
Therapeutics Inc. Amendments will be distributed by the lead institution (Northwestern) to 
all affiliate sites upon approval by the Northwestern University IRB.
11.3
Registration Procedures
For potential patients for this study, study teams are asked to inform the QAM of the date 
and time that the patient will need to be registered 
(croqualityassurance@northwestern.edu).  
BEFORE a patient can be treated on study, please complete and submit the following items 
to confirm eligibility and receive an identification number:

Patient’s signed and dated informed consent form (upload to NOTIS and keep original 
hard copy in a secure location/study chart)

Eligibility checklist (signed and dated by the treating physician – upload to NOTIS)

Eligibility eCRF (complete in NOTIS)

Copy of the pathology report (upload to NOTIS)
The QAM will review all source documentation required to confirm eligibility that is readily 
available in the patient’s electronic medical record (EMR).  Any information that is not 
available in the EMR must be de-identified and emailed to the QAM. Once the QAM 
confirms the patient is eligible, he or she will register the patient, assign a subject 
identification number, provide a cohort assignment, and send a confirmation of registration 
to involved personnel. Registration will then be complete and the patient may begin study 
treatment. 
11.4
Data Submission
Once a patient is confirmed and registered to the study, eCRFs should be submitted 
according to the study procedures table.  Generally, for all phase II patients, data are due 
within 10 days of a visit.  A set amount of data may also be requested for any screen 
failures, as is defined by the study. In most instances, this will include collection of 
adverse events and baseline data from the time of registration to the date of screen 
failure. 
11.5
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of 
the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer 
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to NOTIS for additional information). The level of risk attributed to this study requires High 
Risk as outlined in the DSMP. The assigned QAM, with oversight from the Data Monitoring 
Committee, will monitor this study in accordance with the study phase and risk level. 
Please refer to the NOTIS for additional data submission instructions.
11.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol. 
11.6.1
Emergency Modifications
For any such emergency modification implemented, an IRB modification form must 
be completed within 5 business days of making the change, and the QAM must be 
notified within 24 hours of such change. 
11.6.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM using 
the appropriate form.
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that is under the investigator's control and that has 
not been approved by the Institutional Review Board (IRB). Protocol deviations must 
be reported according to the policies and procedures of the IRB of record.
A protocol deviation may be considered an instance of Promptly Reportable Non-
Compliance (PRNC) if it:

Has harmed or increased the risk of harm to one or more research participants.

Has compromised the rights and welfare of the research subject

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
11.7
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study patients. 
The PI must assure that all study site personnel, including sub-investigators and other 
study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit verification 
of proper entry of data. The study may also be subject to routine audits by the Audit 
Committee, as outlined in the DSMP. 
11.8
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, abstracts, 
posters, clinicaltrials.gov releases) must be approved in accordance with the DSMC Data 
Release Policies and Processes. The assigned QAM will prepare a preliminary data set for 
DSMC approval no later than 3 months after the study reaches its primary completion date, 
as defined by ClinicalTrials.gov. This is the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical trial concluded according to the pre-specified protocol or was 
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terminated. If the investigator would like data release to be approved by the DSMC prior to 
when study design specifies, and/or prior to three months after a study’s primary 
completion date, the PI must send a written request for data approval to the QAM which 
includes justification. Requests must be made a minimum of six to eight weeks in advance 
of the expected deadline. The request will be presented to the DSMC at their next available 
meeting. Any DSMC decisions regarding data release will be provided to the PI. If the 
request is approved, the QAM will present the data set to the DSMC for approval. A final, 
DSMC-approved dataset, as applicable, will then be released 6-8 weeks after the request 
was made. The investigators are expected to use only DSMC-approved data and statistical 
analyses any time they are disseminating trial data. The investigators must send a copy of 
the draft abstract/poster/manuscript to the study’s biostatistician and assigned QAM to 
confirm that the DSMC-approved data and statistical analyses are used appropriately. 
Once the biostatistician and QAM gives final approval, the publication may be submitted to 
external publisher.
 
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References
1.
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer Statistics, 2017. CA Cancer J Clin, 2017. 67(1): p. 
7-30.
2.
Harris, W.P., et al., Androgen deprivation therapy: progress in understanding mechanisms of 
resistance and optimizing androgen depletion. Nat Clin Pract Urol, 2009. 6(2): p. 76-85.
3.
Fizazi, K., et al., Abiraterone acetate for treatment of metastatic castration-resistant prostate 
cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-
controlled phase 3 study. Lancet Oncol, 2012. 13(10): p. 983-92.
4.
Rathkopf, D.E., et al., Updated interim efficacy analysis and long-term safety of abiraterone 
acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy 
(COU-AA-302). Eur Urol, 2014. 66(5): p. 815-25.
5.
Scher, H.I., et al., Increased survival with enzalutamide in prostate cancer after chemotherapy. N 
Engl J Med, 2012. 367(13): p. 1187-97.
6.
Berthold, D.R., et al., Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced 
prostate cancer: updated survival in the TAX 327 study. J Clin Oncol, 2008. 26(2): p. 242-5.
7.
de Bono, J.S., et al., Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-
resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. 
Lancet, 2010. 376(9747): p. 1147-54.
8.
Kantoff, P.W., et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl 
J Med, 2010. 363(5): p. 411-22.
9.
West, T.A., B.E. Kiely, and M.R. Stockler, Estimating scenarios for survival time in men starting 
systemic therapies for castration-resistant prostate cancer: a systematic review of randomised 
trials. Eur J Cancer, 2014. 50(11): p. 1916-24.
10.
Bianchini, D., et al., Antitumour activity of enzalutamide (MDV3100) in patients with metastatic 
castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur J 
Cancer, 2014. 50(1): p. 78-84.
11.
Caffo, O., et al., Clinical Outcomes of Castration-resistant Prostate Cancer Treatments 
Administered as Third or Fourth Line Following Failure of Docetaxel and Other Second-line 
Treatment: Results of an Italian Multicentre Study. Eur Urol, 2015. 68(1): p. 147-53.
12.
Boyd, A.W., P.F. Bartlett, and M. Lackmann, Therapeutic targeting of EPH receptors and their 
ligands. Nat Rev Drug Discov, 2014. 13(1): p. 39-62.
13.
Karantanos, T., P.G. Corn, and T.C. Thompson, Prostate cancer progression after androgen 
deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. 
Oncogene, 2013. 32(49): p. 5501-5511.
14.
Kawano, H., et al., A novel feedback mechanism by Ephrin-B1/B2 in T-cell activation involves a 
concentration-dependent switch from costimulation to inhibition. Eur J Immunol, 2012. 42(6): p. 
1562-72.
15.
Shiuan, E. and J. Chen, Eph Receptor Tyrosine Kinases in Tumor Immunity. Cancer Res, 2016.
16.
Wang, B., Cancer cells exploit the Eph-ephrin system to promote invasion and metastasis: tales 
of unwitting partners. Sci Signal, 2011. 4(175): p. pe28.
17.
Xia, G., et al., EphB4 expression and biological significance in prostate cancer. Cancer Res, 
2005. 65(11): p. 4623-32.
18.
Lee, Y.C., et al., Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate 
carcinoma. BMC Cancer, 2005. 5: p. 119.
19.
Grasso, C.S., et al., The mutational landscape of lethal castration-resistant prostate cancer. 
Nature, 2012. 487(7406): p. 239-43.
20.
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2017. CA: A Cancer Journal for 
Clinicians, 2017. 67(1): p. 7-30.
21.
Sweeney, C.J., et al., Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate 
Cancer. New England Journal of Medicine, 2015. 373(8): p. 737-746.
22.
James, N.D., et al., Abiraterone for Prostate Cancer Not Previously Treated with Hormone 
Therapy. New England Journal of Medicine, 2017. 377(4): p. 338-351.
IRB #: STU00209511 Approved by NU IRB for use on or after 3/8/2021 through 3/7/2022.

NU Study Number: NU 18U10
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Version Date: September 16, 2020 (Amendment 6)
23.
Markert, E.K., et al., Molecular classification of prostate cancer using curated expression 
signatures. Proc Natl Acad Sci U S A, 2011. 108(52): p. 21276-81.
24.
El-Khoueiry, A., et al., A first-in-human phase I study of sEphB4-HSA in patients with advanced 
solid tumors with expansion at the maximum tolerated dose (MTD) or recommended phase II 
dose (RP2D). European Journal of Cancer. 69: p. S11.
25.
McCall, J.L., et al., KSR1 and EPHB4 Regulate Myc and PGC1beta To Promote Survival of 
Human Colon Tumors. Mol Cell Biol, 2016. 36(17): p. 2246-61.
26.
Ferguson, B.D., et al., Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway 
Analysis in Lung Cancer. Sci Rep, 2015. 5: p. 10641.
27.
Li, X., et al., The differential expression of EphB2 and EphB4 receptor kinases in normal bladder 
and in transitional cell carcinoma of the bladder. PLoS One, 2014. 9(8): p. e105326.
28.
Mulholland, D.J., et al., Cell autonomous role of PTEN in regulating castration-resistant prostate 
cancer growth. Cancer Cell, 2011. 19(6): p. 792-804.
29.
Noren, N.K., et al., Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates 
tumor growth. Proc Natl Acad Sci U S A, 2004. 101(15): p. 5583-8.
30.
Nguyen, T.M., et al., EphB and Ephrin-B interactions mediate human mesenchymal stem cell 
suppression of activated T-cells. Stem Cells Dev, 2013. 22(20): p. 2751-64.
31.
Bettegowda, C., et al., Detection of circulating tumor DNA in early- and late-stage human 
malignancies. Sci Transl Med, 2014. 6(224): p. 224ra24.
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Version Date: September 16, 2020 (Amendment 6)
12
APPENDICES
12.1
Appendix I: ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking 
hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair.
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12.2
Appendix II: Common Terminology Criteria for Adverse Events V5.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm)
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12.3
Appendix III: Highly Effective 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-relasing

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. Abstinence is not an acceptable 
method 
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12.4
Appendix IV: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Criteria for Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT 
or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
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12.5
Appendix V: Summary of Changes
Amendment 1 – October 22, 2018
SRC Approved - 10/26/18
Section(s) affected
Prior version
Amendment 1 changes
Rationale
Cover page; Section 
7.3.3.3 (Reporting to 
Ephos Biosciences 
Inc); Section 8.1.9 
(Availability & Supply); 
Section 11.2 
(Amendments)
Drug sponsor “Vasgene 
Therapeudics Inc”
Drug Sponsor “Ephos 
Biosciences Inc”
Administrative.  Drug 
company changed 
names.
Amendment 2 – March 4, 2019
SRC Approved - 3/5/19
Section(s) affected
Prior version
Amendment 2 changes
Rationale
Study Summary; 
Section 2.3.1 
(Exploratory 
Objectives); Section 
6.4.1 (Exploratory 
Endpoints)
Exploratory endpoint 
“molecular changes 
associated with EphB4 
and ephrinB2 expression 
in metastatic tumor 
specimens”
Exploratory endpoint: 
“molecular changes 
associated with EphB4 
and ephrinB2 expression 
in tumor specimens 
(primary and/or 
metastatic tissue)”
Updated the 
language to include 
use of primary 
and/or metastatic 
tumor tissue for 
analysis.
Section 1.7 (Rationale 
for exploratory studies)
“sEphB4-HAS”
“sEphB4-HSA”
Corrected error
Section 1.7.2 
(Rationale for 
exploratory studies); 
Section 9.1.2 (EphB4 
activation and other 
associated genes as a 
biomarker for 
response)
Use of the TEMPUS xO 
panel for analysis
Use of the TEMPUS xF 
panel for analysis
After discussion with 
TEMPUS and study 
PIs, xF panel is 
more appropriate for 
analysis.
Section 9 
(Correlatives/Special 
Studies)
IHC analysis performed 
at Northwestern PCF 
and Abdulkadir Lab
IHC analysis performed at 
Abdulkadir Lab
Updated to indicate 
that all IHC analysis 
will be performed in 
Abdulkadir Lab
Amendment 3 – July 24, 2019
SRC Approved -
Section(s) affected
Prior version
Amendment 3 changes
Rationale
n/a
David VanderWeele listed 
as Co-investigator
Administrative 
update
Cover Page
n/a
IND number has been 
added
Administrative 
update
Cover page; Section 
8.1.9 (Availability and 
Supply); Section 11.2 
(Amendments)
Funding source “Ephos 
Biosciences Inc”
Funding Source “Vasgene 
Therapeutics Inc”
Funding sponsor has 
changed their name 
and cover page was 
updated to match 
the study contract 
List of Abbreviations; 
Study Schema; Study 
Summary; Section 
1.7.2 (Rationale for 
Exploratory Endpoints); 
Section 4.1 (Treatment 
Overview); Section 
6.4.2 (Exploratory 
Endpoints); Section 
9.1.3 (Description of 
Correlative studies); 
Section 9.2 (Sample 
Collection)
“circulating tumor DNA 
(ctDNA)”
“cell free DNA (cfDNA)”
Cell free DNA is a 
more accurate term 
than circulating 
tumor DNA since not 
all the circulating 
DNA comes from 
tumor cells. Some is 
from normal cells.
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Study Summary; 
Section 1.5 (Summary 
of clinical trial findings)
Frequency of toxicities 
from the phase 1 study
Updated frequency of 
toxicities from the phase 1 
study
New IB has been 
released with 
updated information 
on toxicities.
Section 1.7.2 
(Rationale for 
Exploratory Endpoints); 
Section 9 
(Correlatives/Special 
Studies); Section 9.1.2 
(EphB4 activation and 
other associated genes 
as a biomarker for 
response); Section 
9.1.3 (The landscape of 
genomic alterations in 
the course of sEphB4 
treatment); 9.4.2 (Next 
Generation 
Sequencing)
Reference to exploratory 
studies using Tempus 
NGS 
Removed mention of 
exploratory studies using 
Tempus NGS.  Samples 
will be stored until final 
analysis center is 
determined.
Contract with 
Tempus is pending 
and this will be 
updated in a later 
amendment. 
Section 3.1.4 (Inclusion 
Criteria) 
“Patients must have 
received at least one first-
line therapy for mCRPC 
and have progressive 
disease (as defined 
below). No more than 3 
prior treatment therapies 
(life prolonging) are 
permitted.”
“Patients must have 
received and progressed 
on at least one second 
generation AR targeted 
therapy for castration 
resistant disease 
irrespective of prior 
chemotherapy. No more 
than 3 prior treatment 
therapies for castration 
resistant disease (life 
prolonging) are permitted.”
FDA Requested 
Change
Clarification of 
inclusion criteria
Section 4.1 (Overview)
Blood samples for 
cytokine collected at 
every cycle.
Blood samples for 
cytokine collected at 
baseline, day 1 of cycle 5 
and disease progression 
or end of treatment.
Blood collection was 
incorrected.
Section 4.3.3 
(Management of 
Infusion Reaction)
n/a
Added instruction for how 
to manage infusion 
reactions
FDA Requested 
Change
Additional instruction 
for how to manage 
infusion reactions 
has been included.
Section 7.3.3.3 
(Reporting to VasGene 
Therapeutics)
SAE reporting to Ephos 
Biosciences
SAE reporting to 
VasGene Therapeutics
Contact information 
for SAE reporting 
has been updated
Section 8.1.6 
(Preparation)
n/a
Bullet point moved under 
section 8.1.6
Corrected formatting 
error
Blood collection on cycle 
3 day 1
Blood collection on cycle 
5 day 1
Corrected error in 
timing of collection
Blood collected in “2 pink 
top EDTA tubes”
Blood collected in “2 10ml 
EDTA tubes”
Corrected the type of 
blood tubes used for 
collection
8 slides needed for IHC 
analysis
Up to 12 slides for IHC 
analysis
Allowed for the 
possibility of 
additional slides to 
be used for IHC.
Section 9 
(Correlatives/Special 
Studies)
Destination of all samples 
was either to Abdulkadir 
Lab or Tempus
All samples will be sent to 
NU PCF-CTU
Updated destination 
of all samples.
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Sarki Abdulkadir listed as 
contact
NU PCF-CTU Listed as 
contact
Administrative 
update. PCF-CTU 
will handle all 
samples.
Instructions for shipping 
of samples
All samples will be 
shipped to NU PCF-CTU
Administrative 
update. PCF-CTU 
will handle all 
samples.
Instructions for storage 
needs
Included instructions for 
long term storage for 
blood samples
Updated instructions 
for sample storage.
Section 9 
(Correlatives/Special 
Studies); Section 9.2 
(Sample Collection 
Guidelines)
N/a
Analysis of tissue samples 
will be prioritized first for 
sequencing and then for 
IHC.
Priority for tissue 
samples has been 
included due to the 
likelihood of low 
tissue volumes.
Section 9.5 (Specimen 
Banking)
Research samples will be 
stored at the Abdulkadir 
Lab
Research samples will be 
stored at the Abdulkadir 
Lab and Northwestern 
University Pathology 
Core Facility
Tissue samples for 
IHC and blood 
serum will be stored 
in the Abdulkadir 
Lab and the tissue 
and blood for 
sequencing will be 
stored at NU PCF-
CTU.
Amendment 4 – January 29, 2020
Section(s) Affected
Prior Version
Amendment 4 Changes
Rationale
Cover Page and 
Throughout
Protocol version dated 
July 24, 2019
Updates protocol version 
date to January 29, 2020 
(Amendment 4)
Administrative 
update
Cover Page and 
Section 9 
(Correlative/Special 
Studies Table)
N/A
Adds hyperlinks to email 
addresses
Administrative 
update
Table of Contents
N/A
Updates page numbers
Administrative 
update
Study Summary and 
Section 10 (Statistical 
Considerations)
Referenced Section 4.9 
for continuous monitoring 
plan using Pocock-type 
boundary
Removes reference to 
Section 4.9
Correction of 
typographical error.
The reference to 
Section 4.9 and the 
Pocock-type 
boundary continuous 
monitoring plan was 
included in error and 
has now been 
removed.
Study Summary
Exploratory objective:
IHC staining for 
expression of EphB4 and 
ephrinB2 in metastatic 
tumor samples and 
correlate the level of 
alteration with the MYC, 
PTEN/PI3K, AR, and p53 
pathways.
Exploratory objective:
IHC staining for 
expression of EphB4 and 
ephrinB2 in tumor 
samples and correlate 
the level of alteration with 
the MYC, PTEN/PI3K, AR, 
and p53 pathways.
Corrects error. Either 
primary or metastatic 
archival tissue may 
be collected for this 
objective.
Study Schema; 
1.7 (Rationale for 
Exploratory Studies);
Patients are to undergo 
optional biopsy and/or 
provide archival tissue for 
No longer permits fresh 
biopsy for research.
Updates tissue 
collection 
procedures and 
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Exploratory Objective 
2.3.3;
5.0 (Study 
Procedures); 
6.4 (Exploratory 
Endpoints);
9 (Correlatives/Special 
Studies)
next generation 
sequencing (NGS) and 
immunohistochemistry 
(IHC).
Instead of using tissue 
from fresh biopsy, IHC 
data are to be obtained 
from primary and 
metastatic archival tissue, 
if available.
NGS of tumor tissue will 
no longer be performed 
for research; instead, if 
patients have undergone 
molecular testing as a 
standard of care 
procedure, the study will 
analyze genomic 
alterations that are 
described in the results of 
these reports (i.e., results 
from standard of care 
NGS testing/ genetic 
testing/ genomic testing, 
etc.)
analysis for 
feasibility and due to 
budgetary 
constraints
Section 3.1 
(Inclusion Criteria);
Section 5 
(Study Procedures)
Eligibility criteria allowed 
a 28 day window prior to 
registration for select 
screening labs; this was 
not referenced in the 
Study Procedures Table. 
Updates the Study 
Procedures table to clarify 
that screening/baseline 
assessments are to be 
conducted within 1 month 
prior to registration, unless 
otherwise indicated; 
safety labs are to be 
conducted within 2 weeks 
prior to registration; 
updates eligibility criteria 
to align with this by 
specifying a 2 week 
window prior to 
registration for screening 
safety labs.
Clarification 
requested by the 
QAM and PI. 
Section 3.2
(Exclusion Criteria)
N/A
Adds Exclusion Criterion 
3.2.14: Patients with a 
history of significant 
thromboembolic events, 
(including recurrent DVT, 
CVAs, or recurrent 
pulmonary embolism) are 
not eligible.  
Exclusion 3.2.14 has 
been added as a 
cautionary measure 
for safety. sEphB4-
HSA is an 
angiogenesis 
inhibitor. Other 
angiogenesis 
inhibitors can cause 
thromboembolitic 
events.
Section 3.2
(Exclusion Criteria)
N/A
Adds Exclusion Criterion 
3.2.15: Patients with a 
history of any of the 
following are not eligible:
· History of 
noncompliance with other 
medical therapy for 
medical conditions that 
could be impacted by 
study drug-related 
adverse events.
· An illness, condition, or 
other situation that the 
Exclusion 3.2.15 has 
been added to 
ensure compliance 
for patient safety and 
study endpoints.
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treating investigator feels 
would limit compliance 
with study requirements or 
would comprise the 
subject’s safety or study 
endpoints.
Section 5 (Study 
Procedures);
Section 9 (Correlative 
Samples Table)
Permission to obtain 
archival tissue samples of 
primary lesion and 
metastatic lesion sites will 
be obtained at baseline, 
and samples will be 
collected at baseline. 
Permission to obtain 
archival tissue samples of 
primary lesion and 
metastatic lesion sites will 
be obtained at baseline. 
The samples themselves 
will be collected only if 
available and only when 
requested by the Principal 
Investigator or Principal 
Investigator’s designee; 
they may be collected at 
any time during the study, 
per PI request. Refer to 
the lab manual for details.  
Also adds an X to the 
Study Procedures table to 
indicate this collection.
Clarifies the timing of 
collection of archival 
tissue
Section 5 (Study 
Procedures)
Footnote 15 was included 
in the first study 
procedures table but was 
missing from the second 
study procedures table
Adds footnote 15 to the 
second study procedures 
table to align with the first 
study procedures table.
Corrects error. Adds 
missing footnote.
Section 5 (Study 
Procedures)
N/A
Adds footnote 16:
16 If patient has had 
molecular testing (i.e., 
NGS testing, genetic 
testing, genomic testing, 
etc.) performed as 
standard of care prior to 
study entry or at any time 
during study participation, 
collect a copy of the 
results report for 
correlative analyses. 
Refer to Section 9 for 
details.
Updates for 
feasibility and due to 
budgetary 
constraints.  NGS of 
tumor tissue will no 
longer be performed 
in for research; 
instead, if patients 
have undergone 
molecular testing as 
a standard of care 
procedure, the study 
will analyze genomic 
alterations that are 
described in the 
results of these 
reports (i.e., results 
from standard of 
care NGS testing/ 
genetic testing/ 
genomic testing, 
etc.)
Section 7.2.4 
(UPIRSOs)
Previously stated:
A UPIRSO is a type of 
SAE that includes events 
that meet ALL of the 
following criteria:
• Is unanticipated in 
terms of nature, severity, 
or frequency
• Places the research 
Now states:
A UPIRSO is a type of 
SAE that includes events 
that meet ALL of the 
following criteria:
•is unexpected (in terms 
of nature, severity, or 
frequency) given the 
procedures described in 
Updates the 
definition of 
UPIRSO.  This is an 
administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
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subject or others at a 
different or greater risk of 
harm
• Is deemed to be at least 
possibly related to 
participation in the study.    
the research protocol 
documents (e.g., the IRB-
approved research 
protocol and informed 
consent document) and 
the characteristics of the 
human subject population 
being studied
•is related or possibly 
related to participation in 
the research ("possibly 
related" means there is a 
reasonable possibility that 
the incident, experience, 
or outcome may have 
been caused by the 
procedures involved in the 
research); and 
•suggests that the 
research places human 
subjects or others at a 
greater risk of harm 
(including physical, 
psychological, economic, 
or social harm) than was 
previously known or 
recognized, even if no 
harm has actually 
occurred.
Section 7.3.3.1
(Expedited Reporting of 
SAEs/Other Events)
N/A
Now requires completed 
SAE forms to include 
country of incidence
Updates the 
requirements for 
SAE forms. This is 
an administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 7.3.3.1
(Expedited Reporting of 
SAEs/Other Events)
All SAEs will be reported 
to, and reviewed by, the 
DSMC at their next 
meeting.
All SAEs will be reported 
to, and reviewed by, the 
DSMC per the DSMP.
Updates language 
regarding reviewing 
SAEs by the DSMC. 
This is an 
administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 7.3.3.2
(Reporting to the 
Northwestern IRB)
•Any death of an NU 
subject that is 
unanticipated in nature 
and at least possibly 
related to study 
participation will be 
promptly reported to the 
NU IRB within 24 hours 
of notification. 
•Any death of an NU 
subject that is actively on 
study treatment 
(regardless of whether or 
not the event is possibly 
•Any death of an NU 
subject that is 
unanticipated in nature 
and at least possibly 
related to study 
participation will be 
promptly reported to the 
NU IRB within 24 hours of 
notification. 
•Any death of a non-NU 
subject that is 
unanticipated and at least 
possibly related and any 
other UPIRSOs will be 
Updates language 
regarding the 
reporting of SAEs to 
the NU IRB. This is 
an administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
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related to study 
treatment)
•Any death of a non-NU 
subject that is 
unanticipated and at least 
possibly related and any 
other UPIRSOs will be 
reported to the NU IRB 
within 5 working days of 
notification.
reported to Northwestern 
University and to the NU 
IRB within 5 working days 
of notification.
•Information pertaining to 
an NU subject that fits into 
any of the categories 
listed on the Reportable 
New Information page will 
be reported to the NU IRB 
within 5 business days of 
knowledge or notification
Section 7.3.3.4
(Reporting to the FDA)
N/A
Adds Section 7.3.3.4 
(Reporting to the FDA)
The FDA will be notified 
within 7 calendar days of 
any SAE that is 
associated with study 
treatment, is unexpected, 
and is fatal or life-
threatening.
The FDA will be notified 
within 15 calendar days of 
any SAE that is 
associated with the study 
treatment, unexpected, 
and serious but not fatal 
or life-threatening. This 
includes any previous 
SAEs that were not 
initially deemed 
reportable, but are later 
determined to meet the 
criteria for reporting (i.e. 
by the DSMC).
All other SAEs will be 
reported on an annual 
basis as part of the annual 
FDA report.
Adds standard 
protocol template 
languge for reporting 
to the FDA.
Section 9.1 
(Description of 
Correlative Studies)
cfDNA will be isolated 
from the blood samples 
and stored for future 
analysis.
cfDNA will be isolated 
from the blood samples 
and stored for future 
analysis and analyzed by 
NGS testing.
Updates language to 
specify that cfDNA 
samples will be used 
for NGS.
Section 9 (Correlative 
Samples Table)
cfDNA blood samples for 
sequencing listed an 
analysis center of TBD
Updates analysis center 
to Northwestern University 
PI decision to 
perform sample 
analysis at 
Northwestern 
University
Section 9 (Correlative 
Samples Table)
Blood samples for 
cytokine analysis listed 
an analysis center of 
Mayo
Updates analysis center 
to the Abdulkadir Lab
Corrects error in 
analysis center. 
Mayo was listed 
incorrectly as a 
typographical error.
Section 9.4.2 (Next 
Generation 
Sequencing)
We will employ TEMPUS 
xO gene panel for 
primary tumor 
samplesequencing. 
cfDNA samples will be 
analyzed by NGS assays 
at Northwestern  
University.
Updates to specify 
that NGS of cfDNA 
samples will be 
performed at 
Northwestern 
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University. 
Section 11.4 (Data 
Submission) 
Once a subject is 
confirmed and registered 
to the study, eCRFs 
should be submitted 
according to the detailed 
data submission 
guidelines (provided in a 
separate document).  For 
all patients, data are due 
at the end of every cycle.  
Once a patient is 
confirmed and registered 
to the study, eCRFs 
should be submitted 
according to the study 
procedures table.  
Generally, for all phase II 
patients, data are due 
within 10 days of a visit.  A 
set amount of data may 
also be requested for any 
screen failures, as is 
defined by the study. In 
most instances, this will 
include collection of 
adverse events and 
baseline data from the 
time of registration to the 
date of screen failure.
Updates language 
regarding data 
submission. This is 
an administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 11.6.2 (Other 
Protocol Deviations)
A protocol deviation is 
any unplanned variance 
from an IRB approved 
protocol that: 
•Is generally noted or 
recognized after it occurs.
•Has no substantive 
effect on the risks to 
research participants.
•Has no substantive 
effect on the scientific 
integrity of the research 
plan or the value of the 
data collected.
•Did not result from willful 
or knowing misconduct 
on the part of the 
investigator(s).
A protocol deviation is any 
change, divergence, or 
departure from the study 
design or procedures of a 
research protocol that is 
under the investigator's 
control and that has not 
been approved by the 
Institutional Review Board 
(IRB). Protocol deviations 
must be reported 
according to the policies 
and procedures of the IRB 
of record.
Updates language 
regarding protocol 
deviations. This is an 
administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 11.8 
(Publication Policy)
All potential publications 
and/or data for potential 
publications (e.g. 
manuscripts, abstracts, 
posters, clinicaltrials.gov 
releases) must be 
approved in accordance 
with the policies and 
processes set forth in the 
Lurie Cancer Center 
DSMP. For trials that 
require high intensity 
monitoring, the assigned 
QAM will prepare a 
preliminary data 
summary (to be approved 
by the DSMC) no later 
than 3 months after the 
study reaches its primary 
completion date (the date 
that the final subject is 
examined or receives an 
intervention for the 
purposes of final data 
All potential publications 
and/or data for potential 
publications (e.g. 
manuscripts, abstracts, 
posters, clinicaltrials.gov 
releases) must be 
approved in accordance 
with the DSMC Data 
Release Policies and 
Processes. The assigned 
QAM will prepare a 
preliminary data set for 
DSMC approval no later 
than 3 months after the 
study reaches its primary 
completion date, as 
defined by 
ClinicalTrials.gov. This is 
the date that the final 
patient was examined or 
received an intervention 
for the purposes of final 
collection of data for the 
primary outcome, whether 
Updates language 
regarding the 
publication policy. 
This is an 
administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
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collection for the primary 
endpoint). If the 
investigator’s wish to 
obtain DSMC-approved 
data prior to this point (or 
prior to the point dictated 
by study design), the PI 
must send a written 
request for data to the 
QAM which includes 
justification. If the request 
is approved, data will be 
provided no later than 4 
weeks after this request 
approval. The data will be 
presented to the DSMC 
at their next available 
meeting, and a final, 
DSMC-approved dataset 
will be released along 
with any DSMC decisions 
regarding publication. 
The investigators are 
expected to use only 
DSMC-approved data in 
future publications. The 
investigators should 
submit a copy of the 
manuscript to the 
biostatistician to confirm 
that the DSMC-approved 
data are used 
appropriately.  Once the 
biostatistician gives final 
approval, the manuscript 
may be submitted to 
external publishers.
the clinical trial concluded 
according to the pre-
specified protocol or was 
terminated. If the 
investigator would like 
data release to be 
approved by the DSMC 
prior to when study design 
specifies, and/or prior to 
three months after a 
study’s primary 
completion date, the PI 
must send a written 
request for data approval 
to the QAM which 
includes justification. 
Requests must be made a 
minimum of six to eight 
weeks in advance of the 
expected deadline. The 
request will be presented 
to the DSMC at their next 
available meeting. Any 
DSMC decisions 
regarding data release will 
be provided to the PI. If 
the request is approved, 
the QAM will present the 
data set to the DSMC for 
approval. A final, DSMC-
approved dataset, as 
applicable, will then be 
released 6-8 weeks after 
the request was made. 
The investigators are 
expected to use only 
DSMC-approved data and 
statistical analyses any 
time they are 
disseminating trial data. 
The investigators must 
send a copy of the draft 
abstract/poster/manuscript 
to the study’s 
biostatistician and 
assigned QAM to confirm 
that the DSMC-approved 
data and statistical 
analyses are used 
appropriately. Once the 
biostatistician and QAM 
gives final approval, the 
publication may be 
submitted to external 
publisher.
Section 12.4 (Appendix 
IV: Response 
Evaluation Criteria in 
Solid Tumors (RECIST) 
1.1)
In addition, volumetric 
analysis will be explored 
by central review for 
response assessment.
Deletes strikethough text:
In addition, volumetric 
analysis will be explored 
by central review for 
response assessment.
Correction of 
typographical error.
Reference to central 
review was included 
in error and has now 
been removed.
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Throughout
N/A
Minor corrections to 
typographical errors, style, 
and formatting
Administrative 
update
Amendment 5 – August 19, 2020
Section(s) Affected
Prior Version
Amendment 5 
Changes
Rationale
Cover Page and 
Throughout
Protocol version dated 
January 29, 2020 
(Amendment 5)
Updates protocol 
version and date to 
August 19, 2020 
(Amendment 5)
Administrative update
Table of Contents
N/A
Updates page numbers
Administrative update
Table 4-2-1          
(Premedications Table)
Premedications were 
not required.
Adds Table 4-2-1 to 
require the below 
premedication 
schedule:
Administer the two 
below pre-medications 
at least 30 minutes 
before the infusion:           
Diphenhydramine, 25 
mg
Acetaminophen, 650 
mg,
* Refer to Section 4.4.3 
for (1) changes to the 
pre-medication regimen 
for patients who 
experience infusion 
reactions and (2) 
management of infusion 
reactions.
Safety update. Adds a 
required premedication 
regimen as a safety 
precaution in response 
to an enrolled subject 
having experienced an 
infusion reaction.
Table 4-2-2          
(Treatment 
Administration 
Summary Table)
N/A
Names the Table        
“Table 4-2-2”
Adds the following text: 
Additional medications 
for prophylaxis and 
supportive care can be 
administered as 
clinically indicated per 
Institutional standards.
Adds the following 
footnote: * Refer to 
Section 4.4.3 for the 
management of infusion 
reactions.
Administrative updates. 
Adds a name to the 
table.
Reiterates what is 
stated in Section 4.2.
Provides a reference to 
Section 4.4.3 for ease 
of use of protocol end-
users.
Section 4.2
(Treatment Plan)
There are no 
specifically required or 
recommended 
supportive care 
medications. However, 
Premedications include 
diphenhydramine and 
acetaminophen as 
described above in 
Table 4-2-1 . Additional 
Safety update. Adds a 
required premedication 
regimen as a safety 
precaution in response 
to an enrolled subject 
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medications for 
supportive care can be 
administered as 
clinically indicated per 
institutional protocol.
medications for 
prophylaxis and 
supportive care can be 
administered as 
clinically indicated per 
institutional protocol.  
having experienced an 
infusion reaction.
Section 4.3.3                     
(Management of 
Infusion Reaction)
Prophylactic 
premedication may be 
given any time after the 
first dose of Cycle 1. 
However, if any subject 
experiences a Grade 3 
infusion reaction, all 
subsequently enrolled 
subjects will be required 
to receive prophylactic 
premedication before all 
infusions of sEphB4-
HAS...
For Grade 2 symptoms: 
(Rash, flushing, 
urticarial, dyspnea, drug 
fever > 38C) Stop the 
sEphB4-HSA infusion, 
begin an i.v. infusion of 
normal saline, and treat 
the subject with 
diphenhydramine 50 mg 
i.v. (or equivalent) 
and/or acetaminophen; 
remain at bedside and 
monitor subject until 
resolution of symptoms. 
Corticosteroid therapy 
may also be 
administered as 
appropriate… 
…The following 
prophylactic 
premedications are 
recommended for future 
infusions: 
Prophylactic 
premedications will be 
administered as 
described in Table       
4-2-1…   
For Grade 2 symptoms: 
(Rash, flushing, 
urticarial, dyspnea, drug 
fever > 38C) Stop the 
sEphB4-HSA infusion, 
begin an i.v. infusion of 
normal saline, and treat 
the subject with 25 mg 
additional 
diphenhydramine (for 
total dose of 50 mg, 
considering prior 
premedication with 25 
mg) i.v. (or equivalent) 
and/or acetaminophen; 
remain at bedside and 
monitor subject until 
resolution of symptoms. 
Corticosteroid therapy 
(e.g., hydrocortisone, 
PRN, or other 
Institutional standard) 
may also be 
administered as 
appropriate. Additional 
supportive care may be 
administered per 
Institutional standard 
practice…
… The following 
prophylactic 
premedications are 
required for future 
infusions: 
Safety updates. 
Adds a required 
premedication regimen 
as a safety precaution 
in response to an 
enrolled subject having 
experienced an infusion 
reaction.
Provides additional 
guidance for the 
management of infusion 
reactions.
Adds a required 
premedication regimen 
as a safety precaution 
in response to an 
enrolled subject having 
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diphenhydramine 50 mg 
(or equivalent), 
acetaminophen, and/or 
corticosteroids should 
be administered at least 
30 minutes before 
additional sEphB4-HSA 
administration… 
diphenhydramine 50 mg 
(or equivalent) and 
acetaminophen 650 mg 
(or equivalent). 
Corticosteroids (e.g., 
hydrocortisone or other 
Institutional standard) 
are also recommended, 
if clinically indicated. 
These premedications 
should be administered 
at least 30 minutes 
before additional 
sEphB4-HSA 
administration.  
experienced an infusion 
reaction.
Section 4.4.
(Concomitant 
Medications / 
Treatments)
There are no known 
concomitant 
medications or 
treatments associated 
or recommended with 
sEphB4-HSA at this 
time.
Required 
premedications are 
described in Table       
4-2-1. There are no 
other known 
concomitant 
medications or 
treatments associated 
or recommended with 
sEphB4-HSA at this 
time.
Safety update. Adds a 
required premedication 
regimen as a safety 
precaution in response 
to an enrolled subject 
having experienced an 
infusion reaction.
Section 5.0           
(Study Procedures 
Table)
Footnote 11:
Patients will receive 
sEphB4-HSA 1000mg 
IV (60min infusion) on 
day 1 of each cycle 
along with continuation 
of androgen deprivation 
therapy.
Footnote 11:
Patients will receive 
sEphB4-HSA 1000mg 
IV (60min infusion) on 
day 1 of each cycle 
along with continuation 
of androgen deprivation 
therapy.  Refer to Table 
4-2-1 for required 
premedication 
regimens.
Safety update. Adds a 
required premedication 
regimen as a safety 
precaution in response 
to an enrolled subject 
having experienced an 
infusion reaction.
Section 8.1.5      
(Protocol Dose 
Specifics)
sEphB4-HSA will be 
given as 1000mg IV 
infusion…
sEphB4-HSA will be 
given as 1000mg IV 
infusion…Refer to Table 
4-2-1 for required 
premedication 
regimens.
Safety update. Adds a 
required premedication 
regimen as a safety 
precaution in response 
to an enrolled subject 
having experienced an 
infusion reaction.
Appendix V          
(Summary of Changes)
N/A
Describes revisions that 
are made in protocol 
Amendment 5
Administrative update
Throughout
N/A
Minor adjustments to 
formatting and style 
throughout to correct 
errors and 
accommodate revisions.
Administrative update
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Amendment 6 – September 18, 2020
Section(s) Affected
Prior Version
Amendment 6 Changes
Rationale
Cover Page and 
Throughout
Protocol version dated 
August 19, 2020 
(Amendment 5)
Updates protocol version 
and date to September 18, 
2020 (Amendment 6)
Administrative 
update
Study Schema
Response assessment:   
Day 1 of odd cycles (PSA) 
and every 8 weeks (imaging)
Response assessment: 

PSA: Day 1 of odd 
cycles 

Imaging: After 2 
months of therapy and 
every 3 months 
thereafter (after 1 year, 
patients with stable 
disease or better may 
have imaging every 4 
months)
Clarifies imaging 
schedule.
Study Summary; 
Treatment Plan
Section 4.1; 
Treatment Plan 
Overview
…imaging will occur every 8 
weeks.  Imaging for 
response assessment can 
be increased to every 12 
weeks if disease is stable for 
≥6 months and can be 
increased to 16 weeks if 
disease is stable for ≥12 
months.
Deletion of strikethrough text 
and addition of bolded text.
…imaging will occur every 8 
weeks. Imaging for response 
assessment can be 
increased to every 12 weeks 
if disease is stable for ≥6 
months and can be 
increased to 16 weeks if 
disease is stable for ≥12 
months. Imaging will occur 
at baseline and 2 months 
after starting therapy; 
thereafter, imaging will be 
conducted every 3 
months. After 1 year, 
imaging can be done 
every 4 months for 
patients with stable 
disease or better. Scans 
may also be conducted at 
any time, if clinically 
indicated.  
Clarifies imaging 
schedule.
Section 4.1; 
Treatment Plan 
Overview
CT scan and/or MRI, bone 
scan will occur every 8 
weeks. Imaging for response 
assessment can be 
increased to every 12 weeks 
if disease is stable for ≥6 
months.  If disease is stable 
for ≥12 months, imaging will 
occur every 16 weeks for the 
remainder of the study.
Deletion of strikethrough text 
and addition of bolded text.
CT scan and/or MRI, bone 
scan will occur every 8 
weeks. Imaging for response 
assessment can be 
increased to every 12 weeks 
if disease is stable for ≥6 
months.  If disease is stable 
for ≥12 months, imaging will 
occur every 16 weeks for the 
remainder of the study. 
Imaging will occur at 
baseline and 2 months 
after starting therapy; 
Clarifies imaging 
schedule.
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thereafter, imaging will be 
conducted every 3 
months. After 1 year, 
imaging can be done 
every 4 months for 
patients with stable 
disease or better. Scans 
may also be conducted at 
any time, if clinically 
indicated.  
Section 5.0           
(Study Procedures 
Table)
Includes reference to 
footnote * for tumor imaging: 
* Can be competed ±3 days 
of drug administration
The Study Procedures table 
included multiple columns 
and “X’s” to indicate the 
timing of imaging 
assessments. 
Deletes reference to 
footnote * for tumor imaging.
Formatting adjustment to the 
Study Procedures Table. 
Merges imaging 
assessments into a single 
column and single “X” for 
clarity.
Clarifies imaging 
schedule and 
corrects 
discrepancy.
Section 5.0           
(Study Procedures 
Table)
Footnote 2: Imaging is to be 
repeated after 4 cycles (8 
weeks).   See table below 
for subsequent imaging.
Deletion of strikethrough text 
and addition of bolded text.
Footnote 2: Imaging is to be 
repeated after 4 cycles (8 
weeks).   See table below 
for subsequent imaging.  
Imaging will occur at 
baseline and 2 months (± 7 
days) after starting 
therapy; thereafter, 
imaging will be conducted 
every 3 months (± 7 days). 
After 1 year, imaging can 
be done every 4 months (± 
7 days) for patients with 
stable disease or better. 
Scans may also be 
conducted at any time, if 
clinically indicated.  
Clarifies imaging 
schedule.
Section 5.0           
(Study Procedures 
Table)
Footnote 12: Imaging for 
response assessment can 
be increased to every 12 
weeks if disease is stable for 
≥ 6 months.  If disease is 
stable for ≥12 months, 
imaging can be increased to 
every 16 weeks. 
Deletion of strikethrough text 
and addition of bolded text.
Footnote 12: Imaging for 
response assessment can 
be increased to every 12 
weeks if disease is stable for 
≥ 6 months.  If disease is 
stable for ≥12 months, 
imaging can be increased to 
every 16 weeks.  Imaging 
will occur at baseline and 
2 months (± 7 days) after 
Clarifies imaging 
schedule.
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starting therapy; 
thereafter, imaging will be 
conducted every 3 months 
(± 7 days). After 1 year, 
imaging can be done 
every 4 months (± 7 days) 
for patients with stable 
disease or better. Scans 
may also be conducted at 
any time, if clinically 
indicated.  
Section 6.1.1 
(Evaluable Patients)
Evaluable for primary 
endpoint of PSA response. 
All patients who received at 
least 1 dose of the study 
drug will be evaluable for 
PSA response.  
Addition of bolded text:
Evaluable for primary 
endpoint of PSA response. 
All patients who received at 
least 1 dose of the study 
drug and who also had a 
followup PSA test 
conducted prior to 
initiating subsequent 
therapy will be evaluable for 
PSA response.  
The definition of 
evaluability for the 
primary endpoint 
has been revised, 
as requested by 
the Data and 
Safety Monitoring 
Committee 
(DSMC).
Section 6.3 
(Assessment of 
Secondary 
Endpoints)
Disease evaluation will be 
assessed every 8 weeks.
Deletion of strikethrough text 
and addition of bolded text:
Disease evaluation will be 
assessed every 8 weeks by 
imaging at baseline and 2 
months after starting 
therapy; thereafter, 
imaging will be conducted 
every 3 months. After 1 
year, imaging can be done 
every 4 months for 
patients with stable 
disease or better. Scans 
may also be conducted at 
any time, if clinically 
indicated.  
Clarifies imaging 
schedule.
Section 6.3 
(Assessment of 
Secondary 
Endpoints)
Radiologic assessment will 
be every 8 weeks. Imaging 
for response assessment 
can be increased to every 
12 weeks if disease is stable 
for ≥6 months.
Deletion of strikethrough text 
and addition of bolded text:
Radiologic assessment will 
be every 8 weeks. Imaging 
for response assessment 
can be increased to every 
12 weeks if disease is stable 
for ≥6 months. Imaging will 
occur at baseline and 2 
months after starting 
therapy; thereafter, 
imaging will be conducted 
every 3 months. After 1 
year, imaging can be done 
every 4 months for 
patients with stable 
disease or better. Scans 
may also be conducted at 
any time, if clinically 
Clarifies imaging 
schedule.
IRB #: STU00209511 Approved by NU IRB for use on or after 3/8/2021 through 3/7/2022.

NU Study Number: NU 18U10
68
Version Date: September 16, 2020 (Amendment 6)
indicated.  
Appendix V          
(Summary of 
Changes)
N/A
Describes revisions that are 
made in protocol 
Amendment 6
Administrative 
update
Throughout
N/A
Minor adjustments to 
formatting, style, and 
grammar throughout to 
correct typographical errors 
and accommodate revisions.
Administrative 
update
IRB #: STU00209511 Approved by NU IRB for use on or after 3/8/2021 through 3/7/2022.