Conditions: Prostate Cancer
Keywords: Prostate Cancer Metastatic Prostate Cancer Castration Resistant Prostate Cancer Metastatic Castration Resistant
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
This research study is being done to measure the clinical benefit of TRC105 in combination with abiraterone or enzalutamide in metastatic, castration-resistant prostate cancer patients who are taking either abiraterone or enzalutamide and showing signs of biochemical progression without radiographic progression. A patient who is progressing on AR-therapy will continue the same AR-therapy on study with the addition of TRC105. The two arms will accrue in parallel and independently.

Detailed description:
This is a Phase II, open-label study of TRC105 (anti-endoglin antibody) in combination with abiraterone or enzalutamide in metastatic, castration-resistant prostate cancer patients who are taking either abiraterone or enzalutamide and showing signs of biochemical progression without radiographic progression. A patient who is progressing on AR-therapy will continue the same AR-therapy on study with the addition of TRC105. The two arms will accrue in parallel and independently.

There will be a 2-week washout of the active AR-targeted therapy prior to initiation of combination therapy. Tumor response should be assessed at a frequency of 8 weeks by CT/MRI chest, abdomen and pelvis as well as bone scan. Patients may continue on therapy until radiographic progression by RECIST 1.1 or PCWG3 criteria.

Arms:
arm 1: Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone arm 2: Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide

Interventions: intervention 1: TRC105 intervention 2: Abiraterone intervention 3: Enzalutamide
Intervention descriptions: intervention 1: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks intervention 2: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105. intervention 3: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.

Protocol document:
Prot_SAP_000.pdf: 
 
 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized 
in writing by the study sponsor. 
 
 
 
IIT2016-16-POSADAS-TRC105 
A phase 2 study of TRC105 (anti-endoglin antibody) with abiraterone and with enzalutamide in 
patients progressing on therapy 
 
Principal Investigator: 
 
Edwin M Posadas, MD FACP 
 
 
 
 
Urologic Oncology Program 
 
 
 
 
Samuel Oschin Comprehensive Cancer Institute 
 
 
 
 
Cedars-Sinai Medical Center 
 
 
 
 
8700 Beverly Blvd, Los Angeles, CA 90048 
 
Co-Investigator(s): 
 
 
Name 
Department/Division 
Robert Figlin, MD FACP 
Division of Hematology/Oncology 
Kevin Scher, MD MBA 
David Hoffman, MD 
Leland Green, MD 
Fred Rosenfelt, MD 
Tower Hematology/Oncology 
Suwicha Limvorasak, PharmD, BCOP 
Investigational Pharmacy 
Mourad Tighiouart, PhD 
Biostatistics 
Amy Oppenheim 
Johanna Han 
Veronica Placencio, PhD 
Research Coordination 
Nancy Moldawer, MSN RN 
Research Nursing 
 
Laboratory-Investigator(s): 
 
 
Name 
Department/Division 
Neil A. Bhowmick, PhD 
(Scientific Lead) 
Leland Chung, PhD 
Division of Hematology/Oncology 
Department of Medicine  
Michael Freeman, PhD 
Beatrice Knudsen, MD-PhD 
Dolores DiVizio, MD-PhD 
Division of Biological Sciences 
Jie-Fu Chen, MD 
Karen Cavassani, PhD 
Veronica Placencio, PhD  
Elisabeth Hodara 
Shirley Cheng 
Alexander Ureno 
Amy Gomez 
 
Hsian-Rong Tseng, PhD 
California Nanosystems Institute 
University of California, Los Angeles 
 
IND Number: 
 
 
134672 
IND Holder Name: 
 
Edwin Posadas, MD 
Funding Source:  
 
Internal; Planned STTR application to NCI with Tracon  
Initial version:  
 
Version 1 dated 24 AUG 2017 
Clinical Trials.gov: 
 
Registration (pending) 
 
 
 
 
Results Reporting (required)  
NCT No.: 
 
 
Pending 


 
 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized 
in writing by the study sponsor. 
 
 
 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: Edwin M Posadas, MD FACP 
 
 
 
Signature: _____________________________  Date: ____________________ 
 
 
Biostatistician Name: Mourad Tighiouart, PhD 
 
 
 
Signature: _____________________________  Date: ____________________ 
 
 
Clinical Reviewer Name: _____________________________ 
 
 
 
Signature: _____________________________  Date: ____________________ 
 
 
 
 


IIT2016-16-POSADAS-TRC105 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ........................................................................................................ 1 
VERSION HISTORY ................................................................................................................. 2 
STUDY SUMMARY ................................................................................................................. 3 
Primary Objectives .........................................................................................................................3 
Secondary Objectives......................................................................................................................3 
STUDY SCHEMA ..................................................................................................................... 4 
1.0 
BACKGROUND AND RATIONALE ................................................................................... 5 
1.1 
Prostate cancer and androgen receptor (AR) inhibition ..........................................................5 
1.2 
Endoglin (CD105) ..................................................................................................................5 
1.3 
Endoglin and prostate cancer ................................................................................................6 
1.4 
TRC105 .................................................................................................................................8 
1.5 
TRC105 and prostate cancer ................................................................................................ 12 
1.6 
Rationale ............................................................................................................................ 13 
2.0 
STUDY OBJECTIVES ..................................................................................................... 14 
2.1 
Primary Objectives ............................................................................................................. 14 
2.2 
Secondary Objectives.......................................................................................................... 14 
2.3 
Exploratory Objectives ........................................................................................................ 14 
3.0 
ENDPOINTS ................................................................................................................ 15 
4.0 
STUDY DESIGN ........................................................................................................... 16 
5.0 
PATIENT ELIGIBILITY ................................................................................................... 16 
5.1 
Inclusion Criteria ................................................................................................................ 16 
5.2 
Exclusion Criteria ................................................................................................................ 16 
6.0 
TREATMENT PLAN ...................................................................................................... 17 
6.1 
Washout for AR-targeted agents ......................................................................................... 17 
6.2 
Dosing plan ........................................................................................................................ 17 
6.3 
Investigational compound................................................................................................... 17 
6.4 
AR-targeted therapy ........................................................................................................... 20 
6.5 
Toxicities and Dosing Delays/Dose Modifications ................................................................ 20 
6.6 
Concomitant Medications/Treatments ................................................................................ 21 
6.7 
Duration of Therapy ........................................................................................................... 21 
6.8 
Duration of study participation ........................................................................................... 21 
6.9 
Removal of Patients from Protocol ...................................................................................... 22 
6.10 
Patient Replacement ....................................................................................................... 22 
6.11 
Study Procedures ............................................................................................................ 22 
6.12 
Time and Events Table ..................................................................................................... 23 
6.13 
Removal of Subjects from Study ...................................................................................... 24 
7.0 
MEASUREMENT OF EFFECT ......................................................................................... 25 
7.1 
Tumor Assessment ............................................................................................................. 25 
7.2 
Definitions.......................................................................................................................... 25 
7.3 
PSA response criteria .......................................................................................................... 27 


IIT2016-16-POSADAS-TRC105 
 
 
7.4 
Safety/tolerability .............................................................................................................. 27 
8.0 
ADVERSE EVENTS ....................................................................................................... 28 
8.1 
Risks of participation .......................................................................................................... 28 
1.2 
Adverse Event Monitoring .................................................................................................. 28 
8.2 
Definitions.......................................................................................................................... 28 
8.3 
Reporting Requirements for Adverse Events........................................................................ 29 
8.4 
Stopping Rules .................................................................................................................... 30 
9.0 
CORRELATIVES/SPECIAL STUDIES ................................................................................ 31 
9.1 
Correlative Studies ............................................................................................................. 31 
9.2 
Research Specimen collection ............................................................................................. 31 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 32 
10.1 
Study design and statistical approach .............................................................................. 32 
10.2 
Measurement of efficacy ................................................................................................. 32 
10.3 
Safety ............................................................................................................................. 33 
11.0 
STUDY MANAGEMENT ............................................................................................ 35 
11.1 
Conflict of Interest .......................................................................................................... 35 
11.2 
Institutional Review Board (IRB) Approval and Consent .................................................... 35 
11.3 
Registration Procedures .................................................................................................. 35 
11.4 
Data Management and Monitoring/Auditing ................................................................... 36 
11.5 
Data and Safety Monitoring ............................................................................................. 36 
11.6 
Record Retention ............................................................................................................ 37 
11.7 
Adherence to Protocol ..................................................................................................... 37 
11.8 
Obligations of Investigators ............................................................................................. 38 
12.0 
REFERENCES ............................................................................................................ 39 
13.0 
APPENDICES ............................................................................................................ 42 
13.1 
Inhibitors of CYP3A4 ........................................................................................................ 42 
13.2 
Inducers of CYP3A4 ......................................................................................................... 42 
 


IIT2016-16-POSADAS-TRC105 
Protocol Version 1 dated 24AUG 2017 
 
1 
 
LIST OF ABBREVIATIONS 
 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBR 
Clinical benefit rate 
CBR2 
Clinical benefit rate at 2 months 
CBR4 
Clinical benefit rate at 4 months 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
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 
 
 
 
 
 
 
 


IIT2016-16-POSADAS-TRC105 
Protocol Version 1 dated 24AUG 2017 
 
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VERSION HISTORY 
 
 


IIT2016-16-POSADAS-TRC105 
Protocol Version 1 dated 24AUG 2017 
 
3 
 
STUDY SUMMARY 
Title 
A prospective study of TRC105 (anti-endoglin antibody) with abiraterone 
or with enzalutamide 
Protocol Number 
IIT2016-16-POSADAS-TRC105 
Phase 
2  
Methodology 
Parallel Bayesian phase 2  
Study Duration 
24 months 
Study Center(s) 
SOCCI and affiliated practices only 
Objectives 
Primary Objectives 
 
To measure clinical benefit of TRC105 with enzalutamide or 
with abiraterone) in patients who have demonstrated 
resistance by rising PSA on that particular agent. 
Secondary Objectives  
 
Describe the adverse events associated with TRC105 and 
abiraterone or enzalutamide.  
 
Measure the impact of the addition of TRC105 to abiraterone 
or enzalutamide on serum PSA concentration. 
 
Measure the effect of the addition of TRC105 to abiraterone or 
enzalutamide by radiographic response (RECIST, Prostate 
Cancer Working Group 3 (PCWG3)[43]) after 2 and 4 months. 
 
Measure the proportion of patients who remain progression 
free by PSA and/or radiographic measurement at 2 and 4 
months after the addition of TRC105 to abiraterone or 
enzalutamide  
 
Number of Subjects 
40 maximum subjects (limited by Bayesian design) 
 
Arm A: patients progressing on Abiraterone by PSA 
Arm E: patients progressing on Enzalutamide by PSA 
 
Diagnosis and Main 
Inclusion Criteria 
Metastatic, castration-resistant prostate cancer actively progressing on 
abiraterone or enzalutamide by PSA  
Adequate organ function 
ECOG PS 0-2 
Study Product(s), Dose, 
Route, Regimen 
TRC105 10 mg weekly x4 then 15 mg/kg q2weeks; abiraterone or 
enzalutamide per standard dosing 
Duration of administration 
Until radiographic progression by RECIST 1.1 or PCWG3 criteria 
Reference therapy 
N/A 
Statistical Methodology 
Bayesian phase 2 per Tighiouart 
 
 
 


IIT2016-16-POSADAS-TRC105 
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4 
 
STUDY SCHEMA 
 
 
 


IIT2016-16-POSADAS-TRC105 
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1.0 
BACKGROUND AND RATIONALE 
1.1 
Prostate cancer and androgen receptor (AR) inhibition 
Prostate cancer (PCa) is the most common, non-cutaneous cancer affecting men in the United States and 
the second leading cause of cancer death in American males.  For those men who do not have disease 
amenable to means of local control, systemic agents are employed to control disease in efforts to extend 
life and improve quality.  Androgen deprivation therapy (ADT) has been used as the primary mode of 
systemic treatment given the dependence of this cancer upon AR-signaling rooted in the embryonic origin 
of the genitourinary tract.  While ADT is typically highly effective initially, most men facing metastatic PCa 
will progress to a state of castration resistance and require additional treatment.  Metastatic, castration-
resistant PCa (mCRPC) is universally recognized as a lethal evolution in PCa biology.  While there are a 
number of approaches being explored and approved for men affected by mCRPC, the use of next-
generation AR-inhibition strategies have been among the most effective and widely used.  Examples of 
such agents include abiraterone acetate and enzalutamide (see below). While these two FDA-approved 
and commercially available agents are effective in many cases, even those men who benefit initially will 
progress to this form of the disease which is no longer well controlled by either (or both) of these drugs.  
Typically, this manifests as rising serum prostate specific antigen (PSA) concentrations and eventually by 
the appearance of new or expanding radiographic lesions.  Given therapeutic alternatives such as 
chemotherapy, means of extending the benefit of ADT, generally well tolerated, would represent an 
important advancement in PCa therapy. 
1.2 
Endoglin (CD105)  
CD105 (endoglin) is a homodimeric cell membrane glycoprotein that was initially identified as a human 
leukemia-associated antigen [1] and later also found on endothelial cells [2, 3]. CD105 is a TGF-β and BMP 
co-receptor that is essential for angiogenesis [4, 5] and CD105 is strongly expressed on the proliferating 
vascular endothelium of solid tumors [3, 6]. All of these properties make CD105 an attractive target for the 
antiangiogenic therapy of cancer [7]. Vascular targeted therapy may more effectively address large 
established tumors than conventional antiangiogenic therapy such as anti-VEGF therapy [8]. In animal 
models, CD105 targeted therapy has demonstrated both vascular targeting effects and antiangiogenic 
effects by inducing regression of established tumors as well as by preventing new tumor formation and 
inhibiting the expansion of existing tumors [3, 9-12]. Therefore, CD105 offers a novel alternative target 
relative to the VEGF inhibitors currently available for antiangiogenesis therapy.  
 
CD105 acts to modulate signaling of multiple kinase receptor complexes of the TGF-β superfamily, 
including TGF-β receptors, bone morphogenic protein (BMP) and activin receptors [13]. Binding of TGF-β 
to CD105 complexed with TGF-β receptors results in phosphorylation of SMAD 2/3 proteins that reinforces 
a quiescent phenotype and inhibits endothelial cell growth. However, activation of CD105 by BMP 
phosphorylates SMAD1/5, thereby overriding the growth inhibitory effects of TGF-β on endothelium. Not 
surprisingly, prevention of BMP binding to CD105 by an anti-CD105 antibody acts synergistically with TGF-
β to inhibit endothelial cell growth [14].  
 
CD105 expression is required for endothelial cell proliferation, and CD105 is upregulated in the setting of 
hypoxia through the induction of hypoxia-inducible factor-1-α (HIF-1-α) [15, 16]. CD105 has also been 
shown to protect hypoxic cells from apoptosis [17]. The expression of CD105 by endothelial cells is 
essential for the development of new vasculature. Targeted inactivation (knockout) of murine CD105 results 
in defective vascular development. Mice lacking CD105 die in utero from defective vascular development 
by gestational day 11 [4].  
 
CD105 is critical for normal human blood vessel development [18]. CD105 haplotype insufficiency causes 
a well-described syndrome known as hereditary hemorrhagic telangiectasia type 1 (HHT-1 or Rendu-Osler-
Weber Syndrome). HHT-1 is a rare autosomal dominant genetic disorder characterized by localized 
angiodysplasia involving the nasal, buccal, gastrointestinal mucosa and skin microvasculature. 
Angiodysplasia also occurs in vessels from internal organs including the lungs, liver and brain [19]. The 


IIT2016-16-POSADAS-TRC105 
Protocol Version 1 dated 24AUG 2017 
 
6 
 
genotype is manifested in utero, but the phenotype does not become apparent until many years following 
birth. Affected patients commonly present with epistaxis 
in the second decade of 
life. The phenotype of this 
disorder is characterized by vascular effects, indicating the specific role of CD105 in the vasculature [20].  
 
CD105 is highly expressed on the proliferating endothelial cells of tumor vessels including lung, breast, 
colorectal, gastric, liver, endometrial, renal cell, head and neck, and ovarian cancers. Until recently, CD105 
expression in adults had been demonstrated on proliferating endothelial cells and proerythroblasts, a red 
blood cell precursor [21]. CD105 expression 
is a prognostic factor 
in solid tumor patients. High microvessel 
density of CD105-positive vessels has been correlated with poor prognosis in clinical studies of breast 
cancer [22, 23], lung cancer [24], prostate cancer [25, 26], colorectal cancer [27, 28], ovarian cancer [29, 
30], gastric cancer [31], endometrial cancer [32], astrocytic brain tumors [33], hepatocellular carcinoma [34], 
esophageal adenocarcinoma [35], and head and neck cancer [36, 37].  
 
Plasma soluble-CD105 (cleaved extracellular domain) is prognostic in retrospective studies of cancer 
patients. In one study, the mean plasma CD105 concentration in 76 patients with colorectal cancer was 4-
fold higher than the mean value 
in 40 healthy subjects without cancer [28]. In the study, a positive correlation 
was observed between plasma soluble-CD105 concentration and stage of disease.  
 
Importantly, CD105 expression is up regulated in tumor endothelial cells following inhibition of the VEGF 
pathway. CD105 expression 
increased more than 2-fold 
in human pancreatic cancers grown 
in mice treated 
with an antibody that binds VEGF [38]. Similarly, treatment of human bladder cancers grown in mice with 
an antibody that blocks activation of the VEGF receptor 
increased CD105 expression within the core tumor 
vasculature [39]. TRC105 
is a novel IgG1 that binds CD105 with high avidity and competitively 
inhibits BMP 
binding to CD105. Recent studies at Duke University explored the in vitro effects of dual angiogenesis 
inhibition using bevacizumab and TRC105 
in human umbilical vein endothelial cells (HUVEC). Combination 
therapy was found to be more potent in decreasing HUVEC proliferation, migration, and tubular network 
formation than bevacizumab or TRC105 treatment alone [40].  Furthermore, TRC105 induced apoptosis in 
HUVEC, while promoting SMAD2/3 phosphorylation and 
inhibiting SMAD1/5/8 signaling, confirming 
its anti-
angiogenic properties. Finally, antibody to mouse CD105 potentiates the activity of multitargeted kinase 
inhibition that targets the VEGFR-2, in 
mouse bearing cancer grafts.  
1.3 
Endoglin and prostate 
cancer 
The Bhowmick lab has found that 
CD105 is expressed in both prostate 
cancer epithelia  and  associated 
fibroblasts.  Furthermore, CD105 
expression on prostatic epithelia and 
associated fibroblasts contributes to 
castrate resistance. Analysis of CD105 
expression by immunohistochemistry 
on a tumor array showed that in benign 
prostate tissue, CD105 is restricted  
to blood vessels (Figure 1). In contrast, 
endothelial cells, epithelial cancer cells, 
and stromal fibroblasts of PCa tissues 
expressed CD105. In addition, patient 
derived tissues, including neoplastic 
cells and associated fibroblasts, were 
grafted into the sub-renal capsules in 
mice to develop patient derived 
xenograft (PDX) models. A subset of 
 
Figure 1.  CD105 is expressed in prostate tissue. 
Immunohistochemical staining for CD105 staining (brown) was 
counterstained with hematoxylin for the indicated tissue 
specimens. A. Representative tissue sections from a tumor 
microarray are shown (n = 48). Arrowheads indicate positive 
blood vessel staining and arrows indicate positive stromal cell 
staining. B. Prostate cancer patient derived xenograft (PDX) 
tissue staining for CD105 
is shown on the 
indicated specimens 
for mice given vehicle control or enzalutamide treatment.
Figure 1. CD105 is expressed in the prostate 
Enzalutamide + 
Vehicle Control 
CD105 
A 
B 
Immunohistochemical staining for CD105 staining (brown) was counterstained with 
hematoxylin for the indicated tissue specimens. A. Representative tissue sections from a 
tumor microarray are shown (n = 48). Arrowheads indicate positive blood vessel staining 
and arrows indicate positive stromal cell staining. B. Prostate cancer patient derived 
xenograft (PDX) tissue staining for CD105 is shown on the indicated specimens for mice 
given vehicle control or enzalutamide treatment.  
Vehicle Control 
 


IIT2016-16-POSADAS-TRC105 
Protocol Version 1 dated 24AUG 2017 
 
7 
 
PDX mice received Enzalutamide treatment. 
CD105 expression was shown to be elevated 
following enzalutamide treatment compared to 
control mice.  
 
Interestingly, antagonizing CD105 has no 
statistically significant effect on prostate 
cancer cell lines (PC3, 22Rv1, LNCaP, C42B) 
and minimal effect on primary prostatic 
fibroblasts in normoxic conditions in vitro (21% 
O2). The treatment of TRC105 to these cells 
did not appreciably change the cell surface 
expression of CD105, as determined by flow 
sorting in normoxic conditions. In contrast, 
under hypoxic conditions (2% O
2), mimicking 
the oxygen concentration found in solid 
tumors, CD105 was elevated dramatically in 
both 22Rv1 epithelia and primary prostate 
fibroblasts 
(Figure  2). 
Furthermore, 
enzalutamide treatment in hypoxia led to 
elevated CD105 levels, similar to those 
observed in mice. Combination treatment of 
TRC105 with enzalutamide decreased these 
elevated 
levels. It has been shown that human  
epithelial 22Rv1 cells xenografted in isolation 
of their stromal CAF counterpart are sensitive 
to enzalutamide therapy.  
 
 
 
 
Figure 2. CD105 expression is elevated due to 
enzalutamide treatment under hypoxic conditions that 
mimic physiologic conditions.  Human prostate cancer 
(PCa) epithelial cells (red boxes) were grown in 3D co-
cultures with mouse fibroblasts (blue boxes) under hypoxia 
(2% O2) with the indicated treatments. After 72 hours, the 
cells were dissociated and assessed by FACS for CD105 
expression as shown. Antagonizing CD105 by either M1043 
or TRC105 down regulated enzalutamide-induced CD105 
cell surface expression in both mouse prostatic fibroblasts 
and human prostate cancer epithelia. 
 
Figure 3. Human prostate cancer CW22Rv1 epithelial cells were orthotopically xenografted with carcinoma 
associated fibroblasts. A. Relative tumor volume (normalized to castrated (Cx) PBS control tumors) is 
plotted for the 
indicated mouse treatment groups. B. Gross pictures of the orthotopic prostate tumors within 
the prostate are shown for the indicated mouse treatment groups. C. Immunohistochemical staining is 
shown for the for the indicated mouse treatment groups. H&E staining in the top panels shows the 
morphology of the prostate tumors. Phosphorylated histone-H3 (PH-H3) indicate cells undergoing mitosis, 
chromagranin A (ChromA) 
indicate neuroendocrine differentiation, and TUNEL is an apoptotic cell marker. 
All tissues were counterstained with hematoxylin (blue).  
F
igure
 3
.
 TRC105
 sens
i
t
ize
 CRPC
 
to
 enza
lu
tam
ide 
C
 
Human
 pros
ta
te
 cancer
 CW22Rv1
 ep
i
the
l
ia
l
 ce
l
ls
 were
 or
tho
top
ica
l
ly xenogra
f
ted w
i
th
 
carc
inoma
 assoc
ia
ted
 f
ibrob
las
ts
.
 A.
 Re
la
t
ive
 tumor
 vo
lume
 (norma
l
ized
 to
 cas
tra
ted
 
(Cx)
 PBS
 con
tro
l
 tumors)
 is
 p
lo
t
ted
 for
 the
 
ind
ica
ted
 mouse
 trea
tmen
t
 groups
.
 B.
 Gross
 
p
ic
tures
 o
f
 the
 or
tho
top
ic pros
ta
te
 tumors
 w
i
th
in
 the
 pros
ta
te
 are
 shown
 for
 the
 
ind
ica
ted
 
mouse
 trea
tmen
t
 groups
.
 C.
 Immunoh
is
tochem
ica
l s
ta
in
ing
 is
 shown
 for
 the
 for
 the
 
ind
ica
ted
 mouse
 trea
tmen
t
 groups
.
 H&E
 s
ta
in
ing
 in
 the
 top
 pane
ls
 shows
 the
 
morpho
logy
 o
f
 the
 pros
ta
te
 tumors
.
 Phosphory
la
ted
 h
is
tone-H3
 (PH-H3)
 (brown)
 in
 the
 
second
 row
 ind
ica
te
 ce
l
ls
 undergo
ing
 m
i
tos
is
,
 chromagran
in A
 (ChromA
)
 (brown)
 in
 the
 
th
ird
 row
 ind
ica
te neuroendocr
ine d
i
f
feren
t
ia
t
ion
, and Term
ina
l deoxynuc
leo
t
idy
l 
trans
ferase dUTP
 neck
 end
 labe
l
ing
 (TUNEL)
 (brown)
 is
 an
 apop
to
t
ic
 ce
l
l
 marker.
 A
l
l
 
t
issues
 were
 coun
ters
ta
ined
 w
i
th
 hema
toxy
l
in
 (b
lue)
.
 
 
 


IIT2016-16-POSADAS-TRC105 
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8 
 
Notably, the Bhowmick lab has shown that xenografts using 22Rv1 cells combined with human cancer 
associated fibroblasts (CAFs) derived from patient biopsies led to resistance of 22Rv1 cells following 
castration or enzalutamide treatment. To further test TRC105 
in the context of an in vivo system that mimics 
the patient population proposed in this clinical trial, human epithelial 22Rv1 cells and CAFs were 
orthotopically xenografted and treated with combinations of castration (similar to abiraterone treatment), 
with or without enzalutamide, and with or without TRC105. Administering TRC105 in the context of 
castration or castration plus enzalutamide resulted in a significant decrease in tumor size compared to 
castration or castration plus enzalutamide (Figure 3). Thus, blockade of CD105 in fibroblasts and cancer 
cells sensitizes the PCa to ADT.  
 
Vascular antagonists have failed 
in various stages of PCa therapy 
in patients. To determine the 
mechanism of action for TRC105 
to be effective, we analyzed the 
resulting 
22Rv1/fibroblast 
xenograft tissues. They were 
found to express elevated levels 
of 
the 
neuroendocrine 
differentiation 
marker 
chromagranin A when treated 
with castration or castration plus 
enzalutamide, which has been 
shown to promote cancer stem 
cell survival. However, the 
addition  of  TRC105 with 
castration plus enzalutamide 
decreased this elevation of 
neuroendocrine  differentiation 
(tumors with TRC105 plus 
castration were too small to 
properly  
evaluate  
by 
immunohistochemistry). 
This 
suggests that TRC105 promoted 
the differentiation of the PCa 
epithelia,  which  makes  it 
sensitive to androgen deprivation 
therapies instead of developing 
castrate  
resistance  
and 
recurrence. To further address 
this mechanism, we have shown 
that  
TRC105 
treatment 
decreased the expression of 
androgen  
receptor  
splice 
variants (AR-v7 in fibroblasts 
and 
AR-v567 in epithelia) induced by 
enzalutamide (Figure 4). 
1.4 
TRC105 
1.4.1 Background 
TRC105 is a genetically engineered human/murine chimeric monoclonal antibody directed against human 
CD105 developed by Tracon pharmaceuticals. The antibody is an IgG1 kappa immunoglobulin containing 
murine variable region sequences and human constant region sequences [41]. TRC105 has an 
approximate molecular weight of 148 kDa. TRC105 has a binding avidity for human CD105 of approximately 
5 pM. TRC105 is formulated in a histidine buffer at a concentration of 25 mg/mL.  
 
Figure 4. Androgen receptor variants upregulated by androgen 
deprivation therapy are inhibited by TRC105. 
A. A diagram of the 
various AR splice variants is shown. B. Human prostate epithelial cell 
line CW22Rv1 or primary prostate carcinoma associated fibroblasts 
(CAF) were treated with control (Ctrl) or enzalutamide (Enza) and 
checked for mRNA expression of various AR splice variants as 
indicated and GAPDH control expression. 
C. CW22Rv1 and CAF cells 
were treated with control or TRC105 (TRC) and assessed for the 
indicated mRNA expression of AR splice variants and Notch 
downstream signaling proteins (Hey1 and RNPC1) thought to be 
responsible for the changes AR variant expression. Red arrows 
indicate the loss of AR variants with TRC105 treatment. 
Figure 4. Androgen receptor variants upregulated by androgen deprivation 
therapy are inhibited by TRC105 
A 
B 
22Rv1  
CAF1 
C 
A. A diagram of the various AR splice variants is shown. B. Human prostate epithelial 
cell line CW22Rv1 or primary prostate carcinoma associated fibroblasts (CAF) were 
treated with control (Ctrl) or enzalutamide (Enza) and checked for mRNA expression 
of various AR splice variants as indicated and GAPDH control expression. C. 
CW22Rv1 and CAF cells were treated with control or TRC105 (TRC) and assessed for 
the indicated mRNA expression of AR splice variants and Notch downstream signaling 
proteins (Hey1 and RNPC1) thought to be responsible for the changes AR variant 
expression. Red arrows indicate the loss of AR variants with TRC105 treatment. 
 


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SN6j, the murine parent antibody of TRC105, binds to human umbilical vein endothelial cells (HUVECs) 
with nearly identical avidity as TRC105. SN6j has been shown to bind the tumor vasculature of malignant 
tissues including prostate, breast, colon, rectum, kidney and lung cancers and to inhibit the growth of tumor 
xenografts [10]. Reactivity with tumor tissues is most dense on the tumor endothelium, as CD105 is not 
generally expressed on epithelial tumor cells [9]. TRC105 induces ADCC on proliferating HUVECs at low 
concentrations and induces apoptosis and growth inhibition at higher concentrations.  
1.4.2 
TRC105 Clinical experience 
Several studies with TRC105 are underway or have been completed. An open-label, phase 1, multicenter 
study of TRC105 (Study 105ST101) is complete. Fifty patients were treated until disease progression with 
TRC105 at 0.01-15 mg/kg/q2wk or 10-15 mg/kg/wk. Completed studies include a phase 1 study of TRC105 
monotherapy in prostate cancer (Karzai, 2015), phase 1b study of TRC105 in combination with 
bevacizumab, phase 2 studies of TRC105 monotherapy in liver cancer and ovarian cancer, and in 
combination with bevacizumab in glioblastoma multiforme (2 studies) and renal cell carcinoma. Ongoing 
studies include phase 1b/2 studies of TRC105 in combination with sorafenib, a phase 2 study of TRC105 
in combination with axitinib in renal cell carcinoma, and a phase 2 study of TRC105 in combination with 
pazopanib in soft tissue sarcoma.  
 
In Study 105ST101, intensive PK was collected following TRC105 administration on Cycle 1 Day 1 and 
Cycle 2 Day 15 and pre-dose concentrations were taken before dosing in subsequent cycles.  Volume of 
distribution was similar to plasma volume, which was consistent with preclinical toxicokinetics and would 
be expected for an antibody administered intravenously.  AUC increased supra-proportionally with dose 
whereas the Cmax appeared to be dose proportional.  TRC105 clearance was consistent with target 
mediated disposition and decreased clearance at higher doses suggests beginning of target saturation. 
Serum concentrations were achieved continuously at doses of 15 mg/kg every 2 weeks (in most but not all 
patients) and 10 mg/kg weekly (in all patients), and TRC105 accumulated at a dose of 15 mg/kg weekly 
(Figure 5).  Importantly, weekly dosing with 10 mg/kg produced continuous TRC105 serum concentrations 
above the target concentration of 25 μg/mL shown to produce maximum inhibition of HUVEC activation in 
vitro (i.e., maximal inhibition of SMAD1 phosphorylation in response to BMP binding) (Figure 5). 
 
 
Figure 5. Single-dose and multiple dose pharmacokinetic data from Study 105ST101 


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In Study 105ST101, serum samples for evaluation of TRC105 immunogenicity, including HAMA and HACA, 
were collected pre-dose on day 1 of each 28-day cycle, at the end of study, and then at 4 and 12 weeks 
after the end of study visit. 
 
HAMA and HACA data are available from the phase 1 monotherapy TRC105 trial. Neither HAMA nor HACA 
were detected in patients treated with CHO-produced TRC105, which has been used in all trials since 2007 
and will be used in this study. 
 
Further studies of a hybrid dosing scheme by where TRC105 is given weekly at 10 mg/kg for four doses 
and then every two weeks at 15 mg/kg indicated the dose and schedule were tolerable and produced 
continuous TRC105 serum levels above target concentrations in all patients.  This hybrid dosing scheme 
has the advantage of allowing every two week dosing after the initial month of treatment, which improves 
patient convenience. 
 
A total of 50 patients were treated on Study 105ST101 with escalating doses of TRC105 at 0.01, 0.03, 0.1, 
0.3, 1, 3, 10 and 15 mg/kg every two weeks and then 10 and 15 mg/kg weekly. Dose escalation proceeded 
stepwise until the top dose was reached. The maximum tolerated dose was exceeded at 15 mg/kg weekly 
and the recommended phase 2 dose of TRC105 was therefore determined to be 10 mg/kg weekly or 15 
mg/kg every two weeks. Three of 4 patients at 15 mg/kg weekly developed grade 3 hypoproliferative anemia 
(without leucopenia or thrombocytopenia) in cycle 2, and one of the three progressed to grade 4 in cycle 3. 
Anemia was associated with accumulation of TRC105 and characterized by a low reticulocyte production 
index. Additional laboratory and clinical evaluations excluded common causes of anemia including blood 
loss, hemolysis, plasma volume expansion, inadequate erythropoietin, iron deficiency, and vitamin B-12 or 
folate deficiency. The anemia is believed to result from TRC105-mediated suppression of proerythroblasts, 
the only cells in the bone marrow known to express substantial levels of CD105. Anemia was reversible 
and manageable with dose reduction and standard supportive measures including erythropoietin and blood 
transfusion. 
 
Infusion reactions, anemia, fatigue, epistaxis and headache were the most frequently observed adverse 
events considered related to TRC105. The majority of treatment-related adverse events were grade 1 or 2.  
Infusion reactions, among the most common adverse events, were usually with the initial TRC105 dose 
and included one or more of the following signs or symptoms: rigors, bronchospasm, urticaria, hypertension, 
hypotension, tachycardia or bradycardia. Infusion reactions were initially reported at 1 mg/kg every 2 weeks 
for patients receiving TRC105 produced in NS0 cells without premedication. TRC105 produced in CHO 
cells was known to more potently engage ADCC in vitro than TRC105 produced in NS0 cells. Because of 
this, the initial dose level for patients receiving CHO-produced TRC105 was de-escalated to 0.3 mg/kg. 
Despite dose de-escalation, the first two patients at 0.3 mg/kg treated with CHO-produced TRC105 
experienced grade 2 and grade 3 infusion reactions with the first dose in the absence of premedication. 
The protocol was therefore amended to require a dexamethasone-based premedication regimen and 
extend the initial infusion duration from 1 to 4 hours. 
 
The amendment mandating premedication and extended initial infusion duration successfully reduced the 
frequency and severity of infusion reactions and allowed dose escalation to continue. One additional patient 
who received CHO-produced TRC105 at 1 mg/kg developed a grade 3 infusion reaction with the third dose 
given over 2 hours. This patient had experienced a grade 2 infusion reaction when the dose was 
administered over 4 hours. In all three patients with grade 3 infusion reactions, TRC105 was not detectable 
in serum at the time of dosing, which allowed de novo binding of TRC105 to CD105 expressing endothelium 
within the vasculature. Grade 3 infusion reactions were not observed in patients dosed at 10 or 15 mg/kg 
who maintained TRC105 serum levels known to saturate CD105 binding sites for the full dosing interval. At 
dose levels where continuous TRC105 serum levels were achieved, dexamethasone was safely 
discontinued and the infusion duration reduced to 1 hour. 
 
Three patients developed grade 1 cutaneous telangiectasia on the trunk early in the course of therapy, all 
at dose levels of 10 or 15 mg/kg weekly that resulted in continuous serum levels of TRC105 known to 
saturate CD105 sites on human endothelium. Grade 1 or 2 hemorrhage was reported, including intermittent 


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postcoital vaginal bleeding (that also occurred prior to TRC105 treatment), epistaxis, and superficial gingival 
bleeding 
 
 
Grade 1 or 2 headaches were observed, mainly in patients treated at doses of TRC105 above 3 mg/kg.  
Headaches began the day following infusion and were generally manageable with acetaminophen. 
However, grade 2 headache in one patient at 15 mg/kg weekly prompted discontinuation prior to completion 
of the dose-limiting toxicity evaluation period. Fatigue was one of the more common adverse events 
attributable to TRC105 and was more prevalent at doses above 3 mg/kg. 
 
One patient developed dose-limiting toxicity of grade 4 hemorrhage presenting as melena from a gastric 
ulcer within 5 days of the initial TRC105 infusion at 0.1 mg/kg. He discontinued TRC105 treatment, was 
transfused 2 units of packed red blood cells and the bleeding resolved with nonsurgical management by 
the time of upper endoscopy. Serious bleeding was not observed following protocol amendment to exclude 
patients with a history of peptic ulcer disease (unless healing was documented) and patients on ulcerogenic 
medications including nonsteroidal anti-inflammatory drugs. 
 
Classic toxicities associated with VEGF inhibition, including hypertension, proteinuria and thrombosis were 
not prominent. One patient with recurrent anal cancer treated at 0.1 mg/kg developed proteinuria 
considered possibly related to TRC105, but proteinuria was also noted prior to TRC105 dosing. Transient 
hypertension (156/112) without QT changes occurred in a single patient one day following infusion of 15 
mg/kg, and was controlled by a single dose of oral antihypertensive medication. There were no arterial or 
venous thromboembolic events, nor gastrointestinal or other perforations in these patients. 
 
 
Potential Risks of TRC105 
 
Grade 3 anemia has occurred with TRC105 therapy at the recommended phase 2 dose.  All patients treated 
with TRC105 should be monitored closely for anemia and treated appropriately, including the possibility of 
TRC105 dose reductions.  Anemia may be caused by correctable mineral or vitamin deficiency. The anemia 
related to TRC105 is hypoproductive in nature and is reversible with interruption of treatment, transfusion, 
erythropoietin, and other interventions as appropriate. 
 
Gastrointestinal hemorrhage has occurred with TRC105 therapy.  Patients with active ulcer disease or risk 
factors for ulcer disease are excluded from this study.    
 
Grade 1 and 2 cutaneous telangiectasia related to TRC105 occur early in the course of therapy and have 
been the source of gingival bleeding and epistaxis.  Telangiectasia are also seen in patients with hereditary 
hemorrhagic telangiectasia (HHT), a disease of CD105 haplotype insufficiency.  Patients with HHT are at 
risk of hemorrhage from abnormal blood vessels and this could be exacerbated by treatment with TRC105.  
Other contraindications to TRC105 therapy include a history of significant hemorrhage or tumors located in 
the central chest or another location where bleeding is associated with high morbidity.  All patients treated 
with TRC105 should be monitored for signs of hemorrhage and the risks and benefits of drug treatment 
reevaluated in any patient with hemorrhage. 
 
Premedication including the use of glucocorticoids is required prior to infusion of TRC105 to reduce the 
frequency and severity of infusion reactions.  Infusion reactions following TRC105 dosing generally occur 
with the first TRC105 dose and include a grade 4 vasovagal reaction that resolved without sequellae.  Signs 
and symptoms of TRC105 infusion reactions include hypertension, hypotension, dyspnea, bronchospasm, 
chills/rigors, chills, sweats, fever, nausea, tachycardia, bradycardia, EKG changes, flushing, urticaria, 
pruritus, and headache, generally of grade 1 and 2 severity. Potential infusion reactions seen with other 
therapeutic antibodies include angioedema, asthenia, throat irritation, rhinitis, vomiting, joint pain, fatigue 
and neurologic disorders including inflammation of the spine and/or brain.  
 
Hypersensitivity reactions with infusions are a potential risk for sensitized patients, and TRC105 should be 
used with caution in patients with known hypersensitivity to any component of the drug product.  Host anti-
TRC105 antibodies to the murine or human portions of CHO-produced TRC105 are rare.  In general, the 


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risk of immunogenicity to therapeutic chimeric antibodies is small (<10%) and the clinical significance of 
immunogenicity is not well defined.   
 
Grade 3 cerebrovascular hemorrhage resulting in hemiparesis occurred in one patient with hepatocellular 
cancer who was thrombocytopenic (who entered the study with a platelet count of 60,000/uL) in a study of 
TRC105 with sorafenib.  Patients must have a platelet count of > 100,000/uL to enter this study (see 
inclusion criteria). A grade 2 transient ischemic attack was reported in a study of TRC105 and pazopanib. 
Transient Grade 3 hepatic encephalopathy occurred in one patient with cirrhosis and hepatocellular 
carcinoma who received TRC105 in combination with sorafenib.   Grade 3 pancreatitis was also observed 
in this study.  Grade 5 intracranial hemorrhage occurred in one glioblastoma patient with markedly abnormal 
blood clotting parameters in a study of TRC105 with bevacizumab.  A patient with glioblastoma developed 
temporary confusion and slurred speech following treatment with TRC105 and bevacizumab that required 
hospitalization for observation. Another patient with glioblastoma, who underwent resection and had a 
history of an abnormal collection of cerebral spinal fluid, developed a grade 2 cerebral spinal fluid leak. A 
third patient with glioblastoma with a history of recurrent meningitis developed recurrent grade 3 bacterial 
meningitis while treated with bevacizumab and TRC105. 
 
Grade 3 myocardial infarction (non-Q wave infarct associated with hypertension following an infusion 
reaction) was observed in a patient with hepatocellular cancer following treatment with TRC105 that 
resolved without sequellae.  In addition, a Grade 5 myocardial infarction occurred in a patient with coronary 
artery disease who received TRC105 in combination with sorafenib. Patients with evidence of active 
coronary artery disease are excluded from participation in this trial (see exclusion criteria).   
 
Adult respiratory distress syndrome that required temporary intubation occurred in one patient who received 
TRC105 with pazopanib, from which the patient recovered. Of note, interstitial lung disease has been added 
as an adverse drug reaction and warning/precaution to the core safety information for pazopanib. 
Pneumothorax (collapsed lung) has been observed in trials of TRC105 administered with VEGF inhibitors 
in patients with lung metastases. In addition, pnemothorax was observed in one patient, also with lung 
metastases, receiving single-agent TRC105. 
 
Infections have been observed rarely. Grade 3 infected lipoma/cyst was observed in a Phase 2 study of 
TRC105 as a single agent in patients with metastatic bladder cancer. Grade 3 orbital cellulitis and grade 3 
brain abscess were observed in patients treated with TRC105 and bevacizumab and considered possibly 
related to TRC105.  Grade 1 and 2 gingivitis including infection and ulceration has also been observed. 
Overall, infections have been observed in fewer than 5% of patients and have largely been considered 
unrelated to treatment with TRC105. Reversible grade 3 colitis was reported in a patient treated with 
TRC105 and pazopanib. 
 
Grade 1-3 headaches have been observed following TRC105 treatment, generally within hours following 
completion of the initial infusion.  Headaches are throbbing in nature, are not associated with radiographic 
abnormalities, and have responded to treatment with non-steroidal anti-inflammatory agents and to triptans. 
Headaches were particularly common when TRC105 and bevacizumab were initially dosed on the same 
day and were ameliorated when TRC105 was dosed one week following bevacizumab dosing and given 
over two days during the initial week of dosing. 
 
Nasal congestion and periorbital edema have been observed with TRC105 dosing, particularly when dosed 
in combination with bevacizumab.  The edema has been transient in nature and treated with corticosteroids.  
Fatigue of grade 1- 3 severity has been reported following dosing with TRC105. Maculopapular rash and 
skin flushing of grade 1 and grade 2 severity have also been reported.  A patient receiving treatment with 
TRC105 and sorafenib developed self-limited pancreatitis of grade 2 severity. 
 
1.5 
TRC105 and prostate cancer 
There has been a limited experience with TRC105 in prostate cancer.  During the phase I 105ST101, across 
all tumors, stable disease was the best radiographic response reported outcome in 21 of 45 patients.   
Decreases in CEA, PSA, or CA-125 were noted in 7 of 21 patients (33%) and a global decrease in key 


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angiogenic biomarkers was observed with treatment. One patient with castrate-refractory prostate cancer 
has remained on TRC105 treatment for 9 years at a TRC105 dose of 0.01 mg/kg every 2 weeks with an 
ongoing complete PSA response, and resolution of bone pain and bone scan normalization.  
 
A second phase I study was conducted in prostate cancer by Karzai et al.  This disease focused study used 
a standard 3+3 phase I design and treated a total of 20 patients.  No dose limiting toxicity (DLT) was 
identified.  The maximum dose tested of 20 mg/kg every 2 weeks was declared the maximum tolerated 
dose (MTD).  Common adverse effects included infusion-related reaction (90%), low grade headache 
(67%), anemia (48%), epistaxis (43%) and fever (43%). Ten patients had stable disease on study and eight 
patients had declines in prostate specific antigen (PSA). Vascular endothelial growth factor (VEGF) was 
increased after treatment with TRC105. 
1.6 
Rationale 
The Bhowmick laboratory has shown that TRC105 inhibits multiple biochemical changes that promote the 
onset of resistance to AR-targeted therapies.  Models of AR inhibition (blocking androgen synthesis and 
androgen receptor antagonism) result in CD105 upregulation in prostate cancer epithelia and associated 
stromal cells. CD105 expression can stimulate tumor vascular and fibroblast proliferation as well as mediate 
tumor expression of androgen receptor variants resistant to AR-targeted therapies. TRC105, as a single 
agent, was not inhibitory to PCa expansion in CRPC patients [42]. Accordingly, we anticipate a combination 
of AR-targeted therapy (enzalutamide or abiraterone) with TRC105 (in patients with rising PSA) will inhibit 
PCa tumor progression. In tissue culture and tissue recombination studies in mice, CD105 was elevated 
with enzalutamide treatment and importantly was suppressed with TRC105 treatment. Similarly, human 
PCa xenografted castrated mice treated with TRC105, demonstrated decreased tumor volume compared 
to castration alone (similar to abiraterone) or castration plus enzalutamide. In tumor tissues of mice treated 
with TRC105, tumor epithelial cells showed a decrease in neuroendocrine differentiation- a suspected mode 
of resistance to AR-targeted therapy. Furthermore, TRC105 treatment decreased the expression of AR 
therapy-induced splice variant generation (AR-V7) in PCa epithelia and fibroblasts. Such expression of 
androgen receptor splice variants lacking the ligand binding domain are transcriptionally active in the 
context of AR-targeted therapies. This data supports the use of TRC105 in combination with AR-targeted 
therapies (enzalutamide or abiraterone) to suppress factors promoting resistance to AR-targeted therapies 
in both the PCa epithelia and fibroblasts to effectively treat PCa. 
 
Hypotheses 
In light of the above findings, we hypothesize that inhibition of CD105 can overcome resistance to AR 
targeted therapy inducing clinical benefit (including PSA decline) in patients who have developed early 
resistance to AR-targeted therapy 
 
To test this hypothesis, we will conduct a clinical trial to test the addition to TRC105 to two existing AR-
targeted therapies with differing mechanisms and pharmacokinetics: abiraterone and enzalutamide. 
 
 


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2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
To measure clinical benefit of TRC105 with enzalutamide or with abiraterone in patients who 
have demonstrated resistance by rising PSA on that particular agent. 
2.2 
Secondary Objectives  
 
Describe the adverse events associated with TRC105 and abiraterone or enzalutamide.  
 
Measure the impact of the addition of TRC105 to abiraterone or enzalutamide on serum PSA 
concentration. 
 
Measure the effect of the addition of TRC105 to abiraterone or enzalutamide by radiographic 
response (RECIST, Prostate Cancer Working Group 3 (PCWG3)[43]) after 2 and 4 months. 
 
Measure the proportion of patients who remain progression free by PSA and/or radiographic 
measurement at 2 and 4 months after the addition of TRC105 to abiraterone or enzalutamide  
2.3 
Exploratory Objectives  
 
When possible, to obtain archival biopsy tissue specimens on primary tumor and subsequent 
metastasis biopsies preceding the current trial. 
 
Measure the impact of the addition of TRC105 to abiraterone on serum DHEA-S and other 
steroid metabolites and/or intermediates. 
 
Measure the impact of the addition of TRC105 to enzalutamide on serum testosterone and 
other steroid metabolites and/or intermediates. 
 
Measure the impact of the addition of TRC105 to enzalutamide or abiraterone on PFA (platelet 
function). 
 
To associate changes in biomarkers with clinical behavior on combination therapy including 
Nanovelcro and CellSearch CTCs and associated subsets within the CTCs 
 
 
rtPCR for AR status (full length AR and variants AR-V7, AR-v567es, AR-V1, AR45, 
and AR-V3) 
 
Immunofluorescence for RNPC1, Phosphorylated-Smad1/5 and phosphorylated-
Smad2/3, Neuropilin, NE differentiation markers (Chromagranin A, Synaptophysin, 
NSE), EMT markers (E-cadherin, N-cadherin, Snail, Twist), sCD105  
 
To associate changes in serum biomarkers with clinical behavior on combination therapy 
including 
 
sCD105,  
 
Cysteine 
 
P1GF, bFGF, sVEGFR1 
 
Osteopontin 
 
P1NP 
 
CTX 
 
RANKL 
 
PTHrP, PTH 
 
OPG 
 
To associate changes in cells within the buffy coat with clinical behavior on combination therapy 
including 
 
T cells (CD4, CD8, activation markers, and PD-1) 
 
Monocytes expanded and differentiated to macrophage (CD68, CD206 (M2), 
CD62(activation), MHC class II (M1)) 
 
When possible, to associate tissue changes and biomarker expression with clinical outcomes 
including: 
 
Proliferation (by Ki67) 
 
Apoptosis (TUNEL, caspase-3) 
 
NE differentiation 
 
Biochemical markers of stemness 


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 
AR Status  
 
Phosphorylated-Smad1/5 and phosphorylated-Smad2/3 
 
Tumor neo-vascularization (CD31, von willbrand factor) 
 
LOX (measure of hypoxia) 
 
EMT markers (E-cadherin, N-cadherin, Snail, Twist) 
3.0 
ENDPOINTS 
3.1.1 
Primary endpoint 
 
Clinical benefit will be defined as stabilization of disease for at least 2 months or improvement 
at any time from the start of combination therapy by radiographic and/or biochemical criteria.  
o 
Radiographic Improvement will be defined as a PR or CR by RECIST 1.1 or 
improvement by PCWG3 criteria (see section 7.1).  
o 
Biochemical response will be defined by PCGW3 criteria (see section 7.3) 
o 
Stabilization will be defined as the absence of progression by BOTH radiographic and 
biochemical criteria 
3.1.2 
Secondary endpoints 
 
Adverse events from TRC105 and abiraterone or enzalutamide described using CTCAE 4.0 
 
Measurement of progression free survival by PSA and radiographic criteria (as noted above) 
 
 
 


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4.0 
STUDY DESIGN 
 
This is a single-institution, open-label study of TRC105 in combination with abiraterone or enzalutamide in 
patients who are taking either abiraterone or enzalutamide and showing signs of biochemical progression 
without radiographic progression.  In essence, a patient who is progression on AR-therapy will continue the 
same AR-therapy on study with the addition of TRC105. The two arms will accrue in parallel and 
independently. 
 
There will be a 2-week washout of the active AR-targeted therapy prior to initiation of combination therapy.  
TRC105 will be administered at 10 mg/kg weekly for the first 4 weeks then every two weeks at 15 mg/kg.   
 
The first TRC105 dose will be split into two doses whereby 3 mg/kg is administered over 4 hours (+/- 15 
minutes) on Cycle 1 Day 1 and the balance is administered on Cycle 1 Day 4.   
5.0 
PATIENT ELIGIBILITY 
5.1 
Inclusion Criteria 
1. History of metastatic, castration-resistant prostate cancer with rising PSA on either abiraterone or 
enzalutamide 
a. PSA rise will be defined as an increase in PSA of 0.2 ng/mL or higher on at least 2 separate 
occasions greater than 1 week apart while on either abiraterone or enzalutamide 
b. If there is a drop in serum PSA after the first rise, and the patient has another PSA rise 
which is greater than the first, the patient will still be considered eligible. 
2. ECOG 0-2 
3. Resolution of adverse events results from prior cancer therapies to NCI CTCAE grade 1 OR 
baseline with the exception of the laboratory tests specified below. 
4. Adequate organ function defined by: 
 
AST and ALT < 2.5 x ULN 
 
Total serum bilirubin < 1.5 x ULN 
 
Platelets > 100K 
 
Hgb > 8.5 g/dL 
 
Serum Cr <1.5 x ULN 
 
INR 0.8 – 1.2 
5.2 
Exclusion Criteria 
1. Non-PSA producing prostate cancers- such as small cell prostate cancers or those prostate 
cancers which exhibit radiographic progression without PSA rise 
2. Inability to tolerate standard doses of abiraterone (1000 mg daily) or enzalutamide (160 mg daily). 
3. Other prior malignancy requiring active anticancer therapy 
4. Prior exposure to TRC105 or any CD105 targeted antibody 
5. Any major surgical procedure within 2 weeks of starting therapy 
6. Uncontrolled chronic hypertension defined by systolic pressure (SBP) >150 mmHg or diastolic 
pressure (DBP) >90 despite optimal therapy that is present in more than 3 readings taken no less 
than 10 minutes apart. 
7. Active bleeding or pathologic conditions that carries a high bleeding risk 
8. Use of thrombolytics within 10 days prior to the first day of TRC105 
9. Known hypersensitivity to Chinese hamster ovary products or other recombinant human, chimeric, 
or humanized antibodies 
10. A known diagnosis of Osler-Weber-Rendu syndrome 
11. Ascites or pericardial or pleural effusion requiring external drainage procedures 
12. History of untreated brain involvement with cancer, spinal cord compression, or carcinomatous 
meningitis, or new evidence of brain or leptomeningeal disease.  Patients with radiated or resected 
lesions are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, 
and no steroids have been administered for at least 28 days. Imaging for CNS disease will not be 


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required for screening unless there is a history of a neurological finding such as new onset 
weakness or numbness that cannot be explained by other medical history. 
13. Acute cardiovascular event within the past 6 months.  An acute cardiovascular event will be defined 
as a myocardial infraction, NYHA Class II or worse congestive heart failure, cerebrovascular 
accident, transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous 
transluminal coronary angioplasty (PTCA), or CABG. Deep venous thrombosis within 6 months, 
unless the patient is anti-coagulated without the use of warfarin for at least 2 weeks. In this situation, 
low molecular weight heparin is preferred.  
14. Patients must be surgically sterile or must agree to use effective contraception during the study 
and for 3 months following last dose of TRC105.  The definition of effective contraception will be 
based on the judgment of the Principal Investigator or a designated associate.  Abstinence from 
intercourse is an acceptable form of contraception. 
6.0 
TREATMENT PLAN 
6.1 
Washout for AR-targeted agents 
To maximally “reset” AR-driven signaling, patients will be required to have a washout of the AR-targeted 
agent prior to starting study treatment.  Pre-clinical studies demonstrated an induction of CD105 following 
androgen targeted therapy given to naïve tumors. This suggests that TRC105 effects may be maximized 
following a washout period. This washout period will consist of at least 2 weeks prior to starting combination 
therapy.  
6.2 
Dosing plan 
Table 1.  Dosing of AR agent and TRC105 
AR Agent at entry 
AR agent dose 
TRC105 dose 
(weeks 1-4) 
TRC105 dose 
(weeks 5 +) 
Abiraterone 
Abiraterone 1000 mg daily 
10 mg/kg weekly 
15 mg/kg every two weeks 
Enzalutamide 
Enzalutamide 160 mg daily 
10 mg/kg weekly 
15 mg/kg every two weeks 
 
6.3 
Investigational compound 
Composition of TRC105 
TRC105 is an IgG1, kappa immunoglobulin containing murine light- and heavy-chain variable 
region sequences and human constant region sequences. TRC105 has an approximate molecular weight 
of 148 kDa. 
 
TRC105 Packaging and Labeling 
TRC105 may be provided in one or more of the following presentations. 
Phosphate Buffered Saline Formulation (7 mg TRC105/mL)  
210 mg TRC105/30 mL single-use vial 
20 mM L-Histidine/L-Histidine Monohydrochloride, 240 mM Trehalose, 0.01% Polysorbate 20 
Formulation (25 mg TRC105/mL) 
100 mg TRC105/4 mL single-use vial 
200 mg TRC105/8 mL single-use vial 
400 mg TRC105/16 mL single-use vial 
 
TRC105 Storage and Shipping 
TRC105 must be stored upright between 2 °C and 8 °C (36 °F to 46 °F) and protected from light 
 
TRC105 Preparation 
TRC105 will be prepared in the pharmacy and diluted into normal saline using appropriate aseptic 
technique. TRC105 will be administered using an in-line 0.2 micron filter.  No incompatibilities between 
TRC105 and polyvinyl chloride or polyolefin bags have been observed.  Multiple vials will be required for a 


IIT2016-16-POSADAS-TRC105 
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18 
 
single dose.  The following formulae should be used to calculate the volume of TRC105 to be added to 
normal saline: 
 
Patient weight (kg) × dose level (mg/kg) divided by TRC105 concentration (mg/mL) = volume of TRC105 
(mL) to be administered. 
 
The volume of TRC105 that is to be administered can be rounded up or down to the nearest 1.0 mL; in the 
case of an increment of 0.5 mL the volume should be rounded up. The maximum weight that should be 
used for dose calculation for men in this study is 100 kg (note: there is not a weight restriction for 
enrollment purposes).  If the patient’s weight changes by > 10% during the study, the dose of TRC105 
will be recalculated.  At that time a new baseline weight will be established such that subsequent weight 
changes by >10% from the new baseline weight would require further recalculation of the TRC105 dose. 
The calculated volume of TRC105 will be diluted with normal saline.  Appropriate judgment should be 
exercised in withdrawing an adequate amount of saline necessary to permit injection of the appropriate 
volume of antibody into a normal saline bag in accordance with the dose needed.  The final TRC105 
concentration must be between 0.6 mg/mL and 10 mg/mL.  The prepared TRC105 must be gently inverted 
several times in order to ensure a homogeneous solution. The diluted infusion solution of TRC105 should 
be used within 8 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored 
at 2° to 8°C (36º to 46ºF). The expiration time should be labeled on the bag.  If the diluted infusion solution 
of TRC105 cannot be infused within 8 hours of preparation (i.e.: the prepared infusion is at room 
temperature for more than 8 hours), a second bag will be prepared that contains the balance of the planned 
dose that was not already delivered. The prepared solution should not be frozen. 
 
TRC105 Administration 
Patients should be encouraged to drink abundant fluid (e.g., two eight ounce glasses of water or juice) prior 
to the first treatment.  Intravenous hydration prior to and during therapy is left to the discretion of the 
Investigator, but should be considered for patients that may be volume depleted. 
 
The following TRC105 premedications should be administered 2 hours to 30 minutes prior to the start of 
each infusion:   
 
 
Acetaminophen 650 mg p.o. x 1  
 
Methylprednisolone 100 mg IV will be given prior to the cycle 1 day 1 and cycle 1 day 4 infusions.   
In addition, methylprednisolone will be given in the case of a delay of > 10 days between any two 
scheduled weekly doses or in the case of a delay of > 17 days between any two scheduled every 
other week doses, or if the patient develops an infusion reaction > grade 2 during the immediate 
prior infusion.  
 
Famotidine 20 mg IV or p.o. (or similar H2 blocker) x 1. Famotidine (or similar H2 blocker) may be 
discontinued starting with Cycle 3, in the absence of infusion reactions with the prior dose. 
 
Cetirizine 10 mg IV or p.o. x 1 (or similar oral or intravenous antihistamine).  Cetirizine (or similar 
oral or intravenous antihistamine) may be discontinued starting Cycle 3, in the absence of infusion 
reactions with the prior dose. 
 
TRC105 infusions will begin 2 hours to 30 minutes following the completion of the TRC105 
premedication, including the methylprednisolone infusion.     
 
TRC105 will be administered intravenously utilizing an infusion pump.  TRC105 has been demonstrated to 
be compatible with polyethylene lined, non-DEHP infusion sets and polyvinyl chloride, non-DEHP infusion 
sets.  TRC105 is required to be administered with a 0.2 micron downstream filter.  The attachment of the 
infusion pump administration set to the IV bag and transport of the TRC105 study drug to the patient will 
be performed as per standard study site procedures.   
 
Following the appropriate premedication regimen, the first weekly TRC105 dose will be split into two doses 
whereby 3 mg/kg is administered over 4 hours (+/- 15 minutes) on Cycle 1 Day 1 and the balance is 
administered on Cycle 1 Day 4.   
 


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Patients who complete one 4-hour infusion without the development of any infusion reactions, will reduce 
the subsequent TRC105 infusion to 2 hours (+/- 15 minutes) and patients who complete a 2-hour infusion 
without the development of any infusion reactions will reduce subsequent TRC105 infusions to 1 hour (+/- 
15 minutes). See Table 2 for ideal dosing schemas.  Patients with infusion reactions of any kind should be 
managed appropriately and are not permitted to reduce the duration of the next planned infusion. 
 
The rate of TRC105 infusion must not exceed 25 mg/min.  When the IV. bag containing TRC105 is empty, 
flush the IV line with a 20 mL normal saline.  The dose level, time of transfer to IV bag, and the infusion 
start and stop times must be recorded in the source documents. 
 
If a patient misses a scheduled weekly TRC105 dose during the first month of Qweekly dosing and dosing 
is resumed ≥ 10 days after the last dose or if a patient misses a scheduled every 2-week dose after Week 
5, and dosing is resumed ≥ 17 days after the last dose, premedication (including methylprednisolone) are 
to be administered as was done with the initial TRC105 dose. Split dosing is not required. However, it is 
recommended that if the patient experienced a severe headache with a previous infusion, the first TRC105 
dose upon resumption should be administered over two days as was done for the initial dose. 
 
Table 2.  TRC105 doses and schedules for Dose Level A1/E1 
 
C1D1 
C1D4 
C1D8 
C1D15 
C1D22 
C2D1 
C2D15 
C3D1+ 
TRC105 Dose (mg/kg) 
3 
7 
10 
10 
10 
15 
15 
15 
Infusion Duration (hours) 
4 
2 
1 
1 
1 
1 
1 
1 
Premedication 
Methylprednisolone (mg) 
100 
100 
0 
0 
0 
0 
0 
0 
Famotidine (mg) 
20 
20 
20 
20 
20 
20 
20 
0* 
Cetirizine (mg) 
10 
10 
10 
10 
10 
10 
10 
0* 
Acetaminophen (mg) 
650 
650 
650 
650 
650 
650 
650 
650 
 
*  in the absence of infusion reactions with the prior dose, cetirizine and famotidine may be discontinued 
starting at cycle 3 
 
Management of TRC105 Infusion Reactions 
If a patient experiences a grade 2 or high adverse reaction during infusion, the infusion should be interrupted 
and the patient treated accordingly.  Antipyretic, antihistamine, antiemetic, anti-inflammatory or other 
symptomatic medications may be administered as indicated.  For grade 2 and certain grade 3 infusion 
reactions, the infusion may be restarted (the same day) at half of the previous rate after the infusion reaction 
has resolved, then increased per patient tolerance to a maximum of 25 mg/min. For grade 4 infusion 
reactions, the infusion should not be restarted and the patient should be discontinued from study treatment. 
Infusion reactions will be recorded as AEs in the case report form.  
 
 


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Infusion reaction 
severity 
Recommended management 
Grade 1 
No intervention.  Continue infusion unless symptoms worsen 
Grade 2 
1. Interrupt infusion 
2. Treat with symptomatic medications 
3. Resume infusion at half the previous rate when infusion-related 
symptoms improve to grade 1 or less 
Grade 3 
1. Interrupt infusion 
2. Treat with symptomatic medications  
3. Monitor patient until infusion-related symptoms resolve, including 
hospitalization if necessary 
4. Withdraw patient from study unless other factors that contributed to the 
infusion reaction are identified and corrected 
Grade 4 
1. Discontinue infusion 
2. Treat with symptomatic medications 
3. Hospitalize patient 
4. Withdraw from study 
 
Symptomatic medications may include but are not limited to  
 
diphenhydramine 50 mg i.v. and/or hydrocortisone 100 mg i.v. (for fever, rash, hypoxia, or other 
hypersensitivity reactions) 
 
meperidine 50-100 mg i.v. (for shaking chills/rigors),  
 
oxygen by mask or nasal cannula (for hypoxia),  
 
epinephrine 0.5 mg i.m. (for hypotension or bronchospasm),  
 
albuterol inhaler or nebulizer (for bronchospasm),  
 
i.v. fluids (for hypotension),  
 
ondansetron 0.15 mg/kg i.v. (for nausea). 
 
The Investigator must maintain an accurate accounting of TRC105 supplied by Tracon. 
During the study, the following information must be recorded: 
 
Date of receipt, quantity and lot number of the TRC105 study drug received from Tracon 
 
ID number of the patient to whom the product is dispensed 
 
The date(s) and quantity of the product dispensed 
 
Dates and quantity of product returned, lost or accidentally or deliberately destroyed 
6.4 
AR-targeted therapy 
Abiraterone and enzalutamide will not be provided by the study site.  These agents should be prescribed 
as part of standard of care therapy. 
 
Investigational pharmacy will not be responsible for drug accountability of these agents.  Patients will be 
asked to maintain a pill diary to verify dosing per protocol. 
6.5 
Toxicities and Dosing Delays/Dose Modifications 
6.5.1 
AR Therapy 
Dose modifications to AR-therapy will not be allowed. 
6.5.2 
TRC105 Dose Reduction/Dose Interruptions 
TRC105 dose reductions and interruptions should be avoided in cycle 1. In cycle 2 and beyond, TRC105 
dose reductions are allowed using the guidelines below.  TRC105 should be held for two weeks prior and 
for two weeks following surgical procedures. However, resumption of study treatment can be shorter (but 
no less than 7 days) or longer than two weeks based on clinical judgement of the treating investigator of 


IIT2016-16-POSADAS-TRC105 
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21 
 
adequate wound healing and recovery from the procedure. For minor procedures (e.g., port placement), 
TRC105 should be held for at least 1 week prior and for at least 1 week after (or until adequate healing). 
 
Toxicity Attributed to 
TRC105 
Dose Adjustment for Next Dose of TRC105 
(% of Starting Dose) 
Grade 1  
Maintain dose  
Grade 2 
At the discretion of the treating investigator, 
dose may be maintained or decreased to 80%  
Grade 3 or 4 
 
  - first appearance 
Decrease to 80% 
  - second appearance 
Decrease to 60% 
  - third appearance 
Discontinue TRC105 permanently 
6.6 
Concomitant Medications/Treatments 
No other approved or investigational anticancer treatment will be permitted during the study period with the 
exception of primary medical castration therapy (i.e. LHRH analogs). No other investigational drug may be 
used during treatment on this protocol, and concurrent participation in another clinical trial is not allowed. 
 
Patients who are on abiraterone as part of this study should continue to use prednisone 5 mg twice daily or 
an equivalent adrenal androgen supplement at the treating investigator’s discretion.  This dose should be 
stable from the patient’s previous utilization of steroid while on abiraterone.  
 
Patients who receive NSAIDs on study may also receive peptic ulcer disease (PUD) prophylaxis with an 
H2 or proton pump blocker. 
 
Narcotic analgesics, nonsteroidal anti-inflammatory drugs, and triptans (e.g. sumatriptan) may be offered 
as needed for relief of pain or headaches. Antihistamines and decongestants may be offered for the 
treatment of sinus congestion. 
 
Packed red blood cell, colony stimulating factors, and platelet transfusions should be administered as 
clinically indicated. 
 
Patients with arterial thrombosis or grade 3 or 4 venous thrombosis should be removed from the study. 
Patients with grade 1 or 2 venous thrombosis who require anticoagulation will have their TRC105 therapy 
interrupted. TRC105 therapy may resume once the following criteria are met: 
 
The patient is on a stable dose of heparin or low molecular weight heparin or Factor X inhibitor. 
 
The patient has a platelet count > 100,000. 
 
The patient has not had a hemorrhagic event of grade 2 or higher while on study. 
 
The patient does not have a pathological condition that carries a high risk of bleeding (e.g., 
tumor involving major vessels). 
 
The patient is benefiting from TRC105 therapy (no evidence of disease progression). 
6.7 
Duration of Therapy 
Therapy will continue until one of the following: 
 
Disease progression by radiograph or PSA (verified by second rise at least 4 weeks later).  A 
treating physician may continue TRC105 therapy if it is felt that there is clinical benefit despite 
rising PSA. 
 
Patient withdrawal 
 
Excessive toxicity 
 
Death  
6.8 
Duration of study participation 
Patients will have a screening period of 28 days prior to Cycle 1 Day 1. One cycle of therapy consists of 28 
days with any additional time for resolution of adverse events as described. Patients will be treated until 


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disease progression as defined in the protocol or for other reasons of discontinuation as defined in the 
protocol, Section 6.13 .   A 30-day follow-up visit will occur after the last dose of study medication, with the 
allowance for those reasons noted in protocol Section 6.11.3 
6.9 
Removal of Patients from Protocol  
Patients will be removed from the study when any of the criteria listed in Section 6.13 apply. Notify the 
Principal Investigator, and document the reason for study removal and the date the patient was removed 
in the Case Report Form. The patient should be followed-up per protocol.  
6.10 
Patient Replacement 
Patients will not be considered assessable (and hence can be replaced), if they are unable to be assessed 
for clinical benefit at 8 weeks by PSA and/or scans. 
6.11 
Study Procedures 
6.11.1 Screening Phase  
All subjects must sign an informed consent form prior to the conduct of any study-related procedures. 
During this phase the following will be completed as specified in the Time and Event Table: 
 
 
Informed Consent 
 
Investigator’s Confirmation of Eligibility 
 
Demographics 
 
Medical/Surgical History, including treatment history for PCa 
 
Baseline Physical Exam including Performance Status (ECOG) 
 
Vital Signs 
 
PSA 
 
CTC  
 
Serum Testosterone 
 
Urinalysis (w/microscopic examination) 
 
Baseline CT/MRI (Chest CAP or CT Chest/MRI AP) 
 
Bone Scan (Tc-99 or NaF) 
 
Chemistry  
 
Hematology  
 
Concomitant Medications (within 30 days of C1D1) 
6.11.2 Treatment Phase 
The Treatment Phase will begin at Cycle 1 Day 1 of treatment and will continue until study drugs are 
discontinued as per criteria in section 6.13 
 
6.11.3 EOT Visit 
An EOT Visit must be scheduled within 30 days after the last dose of study drug for all subjects, except the 
following: 
 
Patient is lost to follow up 
 
Patient is deceased 
 
Patient has withdrawn consent for study participation. 
 
Patient is unable to return to study site 


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6.12 
Time and Events Table 
 
 
 
Screening 
C1D1 
C1D4 
C1D15 
Day 1 each 
subsequent 
cycle 
(+/- 7) 
Day 15 
each 
subsequent 
cycle (+/- 
7) 
EOT 
30 days 
after 
treatment 
d/c 
(+/- 7) 
Informed Consent 
X 
 
 
 
 
 
 
Medical History & 
Demographics 
X 
 
 
 
 
 
 
History & Physical1 
X 
X 
 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
 
X 
X 
X 
 
Concomitant 
Medications 
X 
X 
 
X 
X 
X 
 
CT or MRI and Bone3 
Scan 
X 
Every 8 weeks from C1D1 
 
 
TRC105 dosing6 
 
X 
X 
X 
X 
X 
 
AR Inhibitor therapy 
 
Continuous daily dosing starting on Cycle 1 Day 1  
 
CBC w/diff  
X 
X 
 
X 
X 
X 
X 
Serum Chemistry4 
X 
X 
 
X 
X 
 
X 
Testosterone, CTC, 
PSA 
X 
X 
 
X 
X 
 
X 
Urinalysis with 
microscopic exam5 
X 
X 
 
 
X 
 
 
Research blood 
collection 
X 
X 
 
 
X 
 
X 
 
1 Documentation should include performance status using ECOG scoring system 
2 Vital signs to include heart rate, temperature, blood pressure, respiratory rate (Height will be assessed during screening only) 
3 CT or MRI scans of chest, abdomen, and pelvis to be performed time points outlined in the time and events schedule of assessments.  
4 Serum chemistry to include, CMPL, LDH (no LDH on C1D15) 
5 Additional urine studies such as protein and/or creatinine should be performed as clinically indicated 
6 See Table 2 for first cycle dosing schedule. 
 


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6.13 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study 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 will be documented and may include: 
 
Patient voluntarily withdraws (follow-up permitted);  
 
Patient withdraws consent (termination of treatment and follow-up); 
 
Patient is unable to comply with protocol requirements; 
 
Patient demonstrates disease progression (unless continued treatment with study drug is 
deemed appropriate at the discretion of the investigator); 
 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
 
Treating physician judges continuation on the study would not be in the patient’s best interest; 
 
Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study; 
 
Lost to follow-up. 
 
 
 
 
 


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7.0 
MEASUREMENT OF EFFECT 
7.1 
Tumor Assessment 
Tumor response should be assessed at a frequency of 8 weeks by standard Tc-99 bone scan and CT of 
the chest, abdomen, and pelvis after the initial assessment, which occurs after the first 8 weeks of study 
treatment.  MRI is an acceptable substitution for CT scans provided that the investigator and subject agree 
to using this as the imaging modality for all soft-tissue tumor assessments for all protocol required imaging 
studies.  
7.1.1 
Bone scan evaluation 
Prostate cancer working group 3 (PCWG3) criteria will be used to evaluate bone scans.   In brief, 
progressive disease will be defined by at least 2 new lesions from a previous scan verified on a subsequent 
scan at least 3 weeks after the original scan.  Increased intensity of lesions on bone scan will not constitute 
disease progression.  
7.1.2 
CT/MRI Assessments: RECIST 1.1 
Response and progression will be evaluated in this study using new response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1) [44]. 
7.2 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment with study 
drug. 
 
Evaluable for objective response. Only those patients who have measurable disease present at baseline, 
have received at least 8 weeks cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response. These patients will have their response classified according to the definitions stated 
below. 
7.2.1 
Disease Parameters 
Measurable disease.  
Lesions must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of 10mm by CT scan or MRI. To be measurable a 
lymph node must be >15mm in short axis when assessed by CT scan or MRI. 
All tumor measurements must be recorded in millimeters. 
 
Note: Previously irradiated lesions are non-measurable except in cases of documented progression of the 
lesion since the completion of radiation therapy. 
 
Non-measurable disease.  
All other lesions, including small lesions (longest diameter<10mm or pathological lymph nodes with >10 to 
<15mm short axis) as well as truly non-measurable lesions are considered non-measurable disease. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ system 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) and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). 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.  
 
The baseline sum diameters will be used as reference by which to characterize the objective tumor 
response. 
 


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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 or absence of each should be noted 
throughout follow-up.  
7.2.2 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric units. 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 when both methods 
have been used to assess the antitumor effect of a treatment. 
7.2.3 
Response Criteria 
 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two separate observations 
conducted not less than 4 weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions plus an 
absolute increase of at least 5 mm, taking as reference the smallest sum recorded since the start of studys.   
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum of diameters since the treatment started. 
 
Evaluation of Best Overall Response 
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. 
 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the 
first date that recurrent disease is objectively documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment started.  
 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of 
progression. 
 
 


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7.3 
PSA response criteria 
While the PCWG3 criteria recommend against decision making based on PSA changes, given the unique 
hypothesis, PSA will be tracked and considered actionable.   
 
Responses will be considered any PSA value >50% below baseline.   
 
Progression will be defined as a rise in serum PSA that is ≥ 25% and 2 ng/mL above nadir which 
is confirmed by a second value ≥ 3 weeks later. 
 
Stabilization of disease refers to PSA values that do not meet criteria for progression 
7.4 
Safety/tolerability 
Analyses will be performed for all patients having received at least one dose of study drug. The study will 
use the CTCAE version 4.0 for reporting of adverse events (http://ctep.cancer.gov/reporting/ctc.html) 
and modified criteria for hematologic adverse events  
 


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8.0 
ADVERSE EVENTS 
8.1 
Risks of participation 
The potential risks of TRC105 therapy are listed in section 1.4.  In addition to the risk of TRC105, during 
the brief washout period, there is a risk of disease progression that is equivalent to the risk of progression 
from remaining on their previous AR-therapy. 
1.2 
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. 
Additionally, certain adverse events must be reported in an expedited manner to allow for optimal 
monitoring of patient safety and care.  
 
AEs (serious and nonserious) will be collected and recorded beginning with the administration of Cycle 1 
Day 1 dosing through 30 days after the last administration of study treatment. If a patient begins a new 
anticancer therapy, the AE reporting period for nonserious AEs ends at the time the new treatment is 
started. 
 
All patients experiencing an adverse event, regardless of its relationship to study drug, will be monitored 
until:  
 
the adverse event resolves or the symptoms or signs that constitute the adverse event return 
to grade 1 or baseline 
 
any clinically significant abnormal laboratory values have returned to grade 1 or baseline 
 
there is a satisfactory explanation other than the study drug for the changes observed 
 
death 
8.2 
Definitions 
8.2.1 
Definition of 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.  
 
Abnormal Test Findings 
Laboratory test and diagnostic studies (e.g. cardiac testing) which meet the following criteria must be 
reported as an AE: 
 
Test result is determined to be clinically significant by the treating investigator or PI 
 
Test result requires medical/surgical intervention 
 
8.2.2 
Severity of Adverse Events 
All adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. The CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
 
Severe (grade 3): the event makes the patient unable to perform normal daily activities or 
significantly affects his/her clinical status. 
 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
 
Fatal (grade 5): the event caused death. 


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8.2.3 
Serious Adverse Events 
A “serious” adverse event is any untoward medical occurrence that: 
 
Results in death: If death results from (progression of) the disease, the disease should not 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 
 
 
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. Steps to Determine If an Adverse Event 
Requires Expedited Reporting 
 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
 
Definite – The AE is clearly related to the study treatment. 
 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment. 
 
Unlikely – The AE is doubtfully related to the study treatment. 
 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Note: 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. 
 
Step 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 known adverse events listed in section 1.4 
 
the drug package insert 
 
the current Investigator’s Brochure 
8.3 
Reporting Requirements for Adverse Events 
8.3.1 
Expedited Reporting 
 
The Principal Investigator must be notified within 24 hours of learning of any serious adverse events, 
regardless of attribution, occurring during the study or within 30 days of the last administration of the 
study drug 
 
 
Phone Number for Expedited Reporting:  Edwin Posadas, MD 310-423-7600 
 
 
The CSMC IRB must be notified within 10 business days of “any unanticipated problems involving risk 
to subjects or others” (UPR/UPIRSO) 
 
 
 


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The following events meet the definition of UPR: 
 
Any serious event (injuries, side effects, deaths or other problems), which in the opinion of the 
Principal Investigator was unanticipated, involved risk to subjects or others, and was possibly 
related to the research procedures. 
 
Any serious accidental or unintentional change to the IRB-approved protocol that alters the 
level of risk. 
 
Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research subject. 
 
Any new information (e.g., publication, safety monitoring report, updated sponsor safety 
report), interim result or other finding that indicates an unexpected change to the risk/benefit 
ratio for the research. 
 
Any breach in confidentiality that may involve risk to the subject or others. 
 
Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved by 
the Principal Investigator. 
 
 
Reporting to the Food and Drug Administration 
The investigator or his designee must submit SAEs on FDA Form 3500A (MedWatch) according to 
the following reporting criteria: 
 
Reporting any unexpected fatal or life-threatening suspected adverse reactions no later than 
7 calendar days after initial receipt of the information. 
 
Reporting any (1) serious, unexpected suspected adverse reactions, (2) findings from other 
clinical, animal, or in-vitro studies that suggest significant human risk, and (3) a clinically 
important increase in the rate of a serious suspected adverse reaction no later than 15 
calendar days after determining that the information qualifies for reporting. 
8.3.2 
Reporting to TRACON 
 
Pregnancy 
Although not itself an SAE, pregnancy will be reported to TRACON and followed up to determine 
outcome, including spontaneous or voluntary termination, details of birth, and the presence or absence of 
any birth defects or congenital abnormalities. 
 
 
Serious Adverse Events 
SAEs will be reported to TRACON no later than 7 business days after initial receipt of the information. 
8.4 
Stopping Rules  
For the phase 2 portion of the study stopping rules for toxicity and futility will be utilized. For safety, we will 
use a Bayesian continuous monitoring design testing for evidence of a high toxicity rate. Specifically, using 
a uniform prior for the probability of toxicity pT, we stop the trial if P(pT > 0.4 |data) > 0.7, that is if the 
posterior probability that the  probability of toxicity is greater than 40% given the data is greater than 0.7. 
Stopping rules for futility are described in the appendix. 
 
 


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9.0 
CORRELATIVES/SPECIAL STUDIES 
 
Details of analyses are listed in the laboratory manual. 
9.1 
Correlative Studies 
The following exploratory correlatives will be examined as part of this study (listed in order of prioritization): 
 
Tissue 
Study/biomarker 
CTCs 
PCR: AR, AR variants 
IHC: 
CD105, 
phosphorylated-SMAD 
1/5, 
NE 
differentiation 
markers 
(Chromagranin A, Synaptophysin, NSE), RNPC1, phosphorylated-Smad2/3, 
total/phosphorylated-STAT-3, YAP, PD-L1, HEY, HES, EMT markers (E-
cadherin, N-cadherin, Snail, Twist),  
Plasma 
soluble CD105, soluble Jag, cysteine, VEGF, IL-6, P1GF, bFGF, sVEGFR1, 
osteopontin, P1NP, CTX, RANKL, PTHrP, PTH, OPG 
WBC (Buffy Coat) 
phosphorylated-SMAD 1/5, HEY/HES, TAK1 
T cells (Buffy Coat) 
CD3, CD4, CD8, CD25, CD28, CD69, PD1 
Monocytes (Buffy 
Coat) 
CD68, CD206 (M2), CD62(activation), MHC class II (M1) 
Tissue biopsy 
(when available and 
feasible) 
PCR: AR variants 
IHC: CD31, CD105, phosphorylated-SMAD 1/5, NE differentiation markers 
(Chromagranin A, Synaptophysin, NSE), RNPC1, total/phosphorylated-STAT-
3, YAP, HEY, HES, phosphorylated-Smad2/3, Ki67, TUNEL, stemness 
markers, LOX, EMT markers (E-cadherin, N-cadherin, Snail, Twist), caspase-3, 
vWF, sCD105. 
9.2 
Research Specimen collection 
9.2.1 
Blood collection 
At specified time points, patients will have research kits collected consisting of the following: 
 
3 yellow top (ACD) tubes- 8.5 mL (25.5 mL total) 
 
1 lavender top tube (EDTA)- 6 mL 
 
Details of collection and processing and analysis are included in the laboratory manual. 
 
9.2.2 
Tissue biopsy 
Patients who are undergoing tissue biopsy as part of their standard clinical care may be asked to provide 
remnant tissue for molecular studies during the course of treatment.  Procurement of the sample will be 
handled as described in the laboratory manual.  
 
 


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10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study design and statistical approach 
The overall hypothesis of this study is that inhibition of CD105 via TRC105 will re-sensitize patients 
progressing on an AR-inhibiting therapy to the same AR inhibitor. 
 
It is unclear which of the two currently used next-generation AR-inhibitors is an optimal partner.  Moreover, 
the preclinical data suggests that the effect should be similar for both agents.  As such, the clinical 
translation of this hypothesis will involve two separate but parallel phase 2 studies.  The two arms (A and 
E) will be merged for the testing of the translational hypothesis.  The two arms will be studied in the clinic 
separately to avoid confusion due to the differences in the AR-inhibitor strategy that may not impact effect 
but may impact other clinically relevant parameters such as toxicity.  The two arms will not be compared 
for effect in the context of this clinical investigation. 
 
In discussion with Tracon, it was decided that the optimal doses for TRC105 is 15 mg/kg administered every 
2 week following the 4-week lead-in consisting of weekly dosing at 10 mg/kg.   Currently Tracon has been 
using the 15 mg/kg q2week dosing in a number of studies.  Specifically, in prostate cancer, 20 mg/kg 
q2weeks has been tested and was found to be well tolerated.  As it is expected that there will be no 
significant interactions based on the pharmacology of agents in question as well as the preclinical models 
from the Bhowmick laboratory, it was decided that there was no advantage to reduction of the AR-targeted 
agent doses.   
 
To optimize toxicity and effectiveness, a Bayesian design was proposed with continuous reassessment of 
both variables over the 2 combinations. 
 
Benefit is judged by proportion of patients experiencing clinical benefit at 2 months [45, 46]. As all patients 
entering this study are progressing on the AR agent already, the null hypothesis will be the proportion of 
patients who benefit will be 0%. To be conservative, we will set the null hypothesis at benefit rate of 5%.  
Conversely, the combination will be declared active if at 2 months of treatment, the proportion of patients 
who benefit is ≥ 50%. 
 
As a matter of contrast, in a reported series, patients previously treated with abiraterone went forward to 
receive subsequent enzalutamide [47].  This group experienced at 63% benefit rate by PSA stabilization or 
response.  Median time to progression (clinical and radiographic) was 5.3 months with a median duration 
of treatment of 4.1 months.  A complementary series was reported of men who received enzalutamide that 
went forward to receive abiraterone [48].  In this group, 70% had clinical benefit by PSA of either stabilization 
or decrease.  Median duration of treatment was 3 months (13 weeks).  No radiographic responses were 
reported. 
 
Additionally, if re-sensitization to AR therapy has occurred, we would expect to see stabilization or 
decreases in serum PSA concentrations.  If at 2 months, the proportion of patients with no meaningful rise 
in PSA is ≥50%, a combination will also be considered worthy of further study. 
 
10.2 
Measurement of efficacy 
The primary endpoint of these phase 2 trials is to show that the clinical benefit (CB) rate for these patients 
is at least 40% with a 5% response rate or lower being uninteresting. Let θ be the probability of CB of the 
new treatment combination. We will use a Bayesian continuous monitoring approach for testing the null 
hypothesis H0: θ = 0.05 versus the alternative hypothesis H1: θ > 0.05. Specifically, we will adapt the 
approach of Johnson and Cook (2009) by placing a point mass prior distribution on θ to represent the null 
hypothesis and an inverse moment prior density with mode at θ = 0.4 to represent the alternative 
hypothesis. 
 


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Johnson and Cook (2009) [49] showed that this design has better operating characteristic than previous 
Bayesian designs which use posterior credible intervals to define stopping boundaries for inferiority and 
superiority. When compared to Simon’s (1989) two-stage design [50], the probabilities of rejecting the 
experimental treatment were similar but this design uses fewer patients to reject treatments that fall below 
the target probability of response relative to Simon’s design. 
 
A maximum of 20 patients per arm will be enrolled in the trial. Assuming that H0 and H1 are equally likely a 
priori, the trial will be terminated after the nth patient for inferiority if the posterior probability of the alternative 
given the data P(H1 |data) < 0.1. At the end of the trial, the alternative hypothesis is accepted if P(H1 |data) 
> 0.9. 
 
Operating Characteristics: 
 
When the true probability of clinical benefit is 0.4, there is at least an 88.6% chance of concluding that the 
treatment is superior which is equivalent to the frequentist statistical power. 
 
Table 5 gives some operating characteristics for testing the above hypothesis under five scenarios for the 
“true” probability of CB θ based on 5,000 trial replications. When the true θ is 0.4, there is a 0.048 probability 
of stopping the trial early for lack of efficacy and this probability is even smaller with smaller values of θ. 
The futility boundaries for stopping the trial early are listed in Table 6. These simulations were carried out 
using the software BFDesigner available at http://biostatistics.mdanderson.org/softwaredownload/. 
 
 
Scenario 
True θ 
Pr(Stopping for 
inferiority) 
Average # patients treated 
(10%, 25%, 50%, 75%, 90%) 
1 
0.05 
0.953 
10.9 (10,10,10,10,10) 
2 
0.15 
0.593 
14.61 (10,10,10,20,20) 
3 
0.25 
0.261 
17.58 (10,20,20,20,20) 
4 
0.4 
0.048 
19.53 (20,20,20,20,20) 
5 
0.5 
0.013 
19.87 (20,20,20,20,20) 
Table 5. Operating Characteristics 
 
 
# Patients 
Stop the trial for inferiority if 
there are this many successes 
10 
0-1 
15 
0-1 
20 
0-2 
Table 6. Full Stopping Boundaries 
 
 
 
10.3 
Safety 
Stopping rules for safety 
 
Let Ptox be the true probability that a patient experiences a grade 3 or higher toxicity related to the treatment 
combination. The trial will stop if there is statistical evidence that Ptox exceeds 40%. We will use a Bayesian 
sequential design by checking whether Ptox exceeds this threshold value after 5, 10, 15, and 20 patients 
are evaluable for toxicity as defined above. The decision rule is to stop the trial if the posterior probability 
that Ptox exceeds 0.40 is 0.95; P(Ptox > 0.4 | data) > 0.95. A noninformative prior distribution for Ptox will be 
used. Table 7 gives the stopping rules for the design at each look and column 2 gives the maximum number 
of patients with toxic events in order for the trial to proceed. For example, if 10 or more toxic related events 
are observed after enrolling 15 patients, the trial stops. The third column gives the probability of stopping 


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the trial when in fact, the true Ptox = 0.40. This is the equivalent of the Bayesian type I error probability. The 
target type I error probability was set at 0.05.  
 
Number of 
Patients 
Number to 
Continue 
Probability to 
Stop 
Cumulative Probability 
to Stop 
5 
4 
0.01024 
0.01024 
10 
7 
0.00904 
0.01928 
15 
9 
0.02388 
0.04316 
20 
12 
0.00609 
0.04925 
 
Table 7.  Stopping rules based on four interim looks. Number to continue is the maximum number of toxic 
events for not stopping the trial. 
 
Table 8 gives the design operating characteristics under selected values of the true probability Ptox. It gives 
the probability of stopping the trial under the alternative hypothesis, the expected sample size, and the 
average sample size given that the trial stopped. For example, if the true value of Ptox is 0.6, then there is 
an 50% chance that the trial is stopped early and the average sample size is about 16. On the other hand, 
there is a small chance of stopping the trial if Ptox is small; 0.67% chance of stopping the trial if in fact Ptox 
= 0.30. 
 
True Value 
of Ptox 
Probability to 
Stop 
Expected 
N 
Expected 
N given that we Stopped 
0.30 
0.0067 
19.94 
10.81 
0.40 
0.0493 
19.64 
12.62 
0.60 
0.5022 
16.53 
13.09 
0.80 
0.9763 
10.16 
9.93 
Table 8.  Design operating characteristics under different scenarios for the true probability of toxicity Ptox.  
 
 
  
 
 


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11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
Any reportable conflict of interest will be disclosed to the local IRB and will be outlined in the Informed 
Consent Form. 
11.2 
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. 
 
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. 
11.3 
Registration Procedures 
 All subjects that sign informed consent and are deemed eligible will be assigned a subject number 
sequentially at the time of registration.  Those subjects that do not pass the screening phase will be listed 
as screen failures on the master list of consented subjects.  Eligible subjects, as determined by screening 
procedures and verified by a treating investigator, will be registered on study at Cedars-Sinai Medical 
Center by the Study Coordinator.   
   
Issues that would cause treatment delays after registration should be discussed with the Principal 
Investigator (PI). If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.   
 
Subjects found to be ineligible will be recorded as screen failures.  Subjects found to be eligible will be 
registered. 
11.3.1 Eligibility Verification 
Prior to registration, all subjects must undergo a secondary eligibility verification by the SOCCI Clinical 
Research Office (CRO). The following documents will be completed and provided for review:  
 
 
Applicable source documents  
 
Eligibility checklist (signed by investigator)  
 
Signed patient consent form and Subject’s Bill of Rights  
 
HIPAA authorization form 
 
 
 
 
 
 


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11.3.2 Registration 
After eligibility is verified, registration is completed as follows: 
• 
Assign a patient study number 
• 
Enter the patient in OnCore 
 
Oversight by the principal investigator is required throughout the entire registration process 
11.4 
Data Management and Monitoring/Auditing 
The data will be entered into a HIPAA-compliant database. The Study Staff will be responsible for data 
processing, in accordance with procedural documentation. Database lock will occur once quality assurance 
procedures have been completed. 
 
All procedures for the handling and analysis of data will be conducted using good computing practices 
meeting FDA guidelines for the handling and analysis of data for clinical trials. 
11.5 
Data and Safety Monitoring 
11.5.1 Data Monitoring and Quality Assurance 
Adherence to the protocol, Good Clinical Practices (GCP), and institutional policy will be monitored by the 
PI during the course of the study through routine Disease Research Group (DRG) meetings or equivalent. 
In addition, the SOCCI CRO Quality Management Core (QMC) will conduct the following:  
 
Audit preparations (AP) prior to audit conducted by any external auditing agency (i.e. NCI or FDA). 
The purpose an AP is to ensure adequate source documentation to support protocol compliance and 
data integrity are present and organized and to identify and correct any major findings prior to the 
external audit 
 
A thorough review of selected subject cases, regulatory files, and IP accountability records (if 
applicable) within 2-3 months after the first subject is enrolled and annually thereafter while subjects 
are receiving investigational intervention.   
 
Central eligibility verification for all subjects enrolled as described in protocol section 11.3.1.   
 
Central review of all eligibility waiver requests by a SOCCI Medical Reviewer to assess 
appropriateness and risk to ensure quality data and ensure subject safety protections for investigator-
initiated research 
 
For any protocol, QMC has the authority to request more frequent reviews or closer safety monitoring if it 
is deemed appropriate for any reason. 
11.5.2 Safety Monitoring 
Oversight of the progress and safety of the study will be provided by the PI. The PI will maintain continuous 
safety monitoring for the duration of the study by reviewing subject/study data. Adverse events and 
unanticipated problems are not expected, but if they occur they will be documented and reported according 
to CSMC IRB policies and procedures. If the PI becomes aware of any new safety information that may 
place subjects at increased risk than what was previously known the IRB will be promptly notified and if 
warranted, enrollment may be held until the PI determines whether a modification to the study is necessary 
and/or the informed consent documents are updated accordingly. 
 
In addition, this protocol will utilize oversight by a Safety Committee On Early Phase Studies (SCOEPS). 
Committee membership includes experts in the field of oncology and early phase studies and biostatistics. 
SCOEPS’ responsibilities are governed by the committee charter, or equivalent.   
 
The SCOEPS will provide routine monitoring of safety and enrollment for all early phase investigator-
initiated trials (IITs). The committee meets routinely and is responsible for reviewing and adjudicating all 
dose-limiting toxicities, dose escalations and appropriateness of the escalation, cohort expansion, subject 
replacements, select AEs, SAEs, and confirmation of attainment of maximum tolerated dose. 
 


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The SCOEPS findings and recommendations will be reported in writing to the Principal Investigator. A 
summary report will be forwarded by the Principal Investigator or his/her designee to the Cedars-Sinai 
Medical Center IRB. 
11.6 
Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, monitoring/auditing logs/letters, and regulatory documents (e.g., protocol and amendments, 
IRB correspondence and approval, signed patient consent forms). 
 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that the study investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. Study documents should be kept on file per local 
guidelines. 
11.7 
Adherence to Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being of 
the study patient requires alternative treatment, or a protocol exception request approved by the SOCCI 
Medical Director and CSMC IRB, the study shall be conducted exactly as described in the approved 
protocol. 
11.7.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB approval. For any such emergency modification implemented, 
the IRB must be notified as soon as possible, but no more than 10 days from the investigator’s awareness 
of the event. 
11.7.2 Protocol Exceptions and Eligibility Waivers  
An exception is an anticipated or planned deviation from the IRB-approved research protocol, as described 
in the IRB Policy, Reporting Possible Unanticipated Problems Involving Risks to Subject or Others 
(UPIRSO) Policy: Institutional Review Board/Research Compliance and Quality Improvement.  
 
A protocol exception most often involves a single subject and is not a permanent revision to the research 
protocol. Protocol exceptions that extend beyond a single subject should result in a protocol amendment to 
avoid serial violations.  
 
All exception requests must be reviewed by the SOCCI CRO Medical Director and the Institutional Review 
Board prior to implementation. The PI or her/his designee is responsible for submitting a protocol exception 
and its supporting documents to the SOCCI Medical Director for review. Planned exceptions to the protocol 
that are more than logistical and/or have the potential to affect the subject’s safety and/or study integrity 
may not be implemented without prior approval from the SOCCI Medical Director and IRB. 
 
 
Special considerations for Eligibility Waivers (EW) 
In general, subjects who do not meet the eligibility requirements should not be enrolled. In the rare event 
that it is appropriate for subject inclusion, the rationale/justification and subject case history should be 
forwarded to the SOCCI CRO Medical Director for assessment prior to submission to the IRB for approval.  
 
The CRO Medical Director will review the case and contact the investigator if additional information is 
needed or further discussion is warranted. The CRO Medical Director will provide a written 
assessment/recommended course of action. The CRO Medical Director’s assessment must be uploaded 
into Webridge with the waiver request for IRB review and consideration. The CRO Medical Director may 
recommend future protocol changes.  
 
 
Eligibility Waiver Submission Process  


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The PI and/or treating physician should provide written request for waiver which includes case history and 
justification for prospective deviation from the study design to the SOCCI CRO Medical Director.  
11.7.3 Other Protocol Deviations 
Logistical deviations from the protocol (e.g., minor changes to the study schedule for an individual subject) 
do not require prior IRB approval unless the deviation has the potential to affect the subject’s safety. Such 
planned deviations that do meet this definition and do not affect the subject’s safety should be noted in the 
subject’s research record or deviation log as described in the SOCCI Clinical Research Office’s Working 
Instruction 11: Deviation and Noncompliance Reporting. 
 
Unintentional deviations from the protocol that might affect subject safety or study integrity should be 
reported to the IRB within 10 days from when the investigator becomes aware that such a deviation has 
occurred, as outlined in the SOCCI Clinical Research Office’s Working Instruction 11: Deviation and 
Noncompliance Reporting. In this case, a Protocol Deviation report must be submitted in Webridge, per 
IRB policy, Reporting Possible Unanticipated Problems Involving Risks to Subject or Others (UPIRSO) 
Policy: Institutional Review Board/Research Compliance and Quality Improvement. All submissions should 
include a description of the plan to avoid similar deviations or exceptions in the future.   
11.7.4 Amendments to the Protocol  
Should amendments to the protocol be required, the amendments will be originated and documented by 
the Principal Investigator. It should also be noted that when an amendment to the protocol substantially 
alters the study design or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the IRB for approval 
prior to implementation. Repeat exceptions or deviations to the protocol may suggest a protocol amendment 
is needed. 
11.8 
Obligations of Investigators 
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 Principal Investigator is 
responsible for personally overseeing the treatment of all study patients. The Principal Investigator 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 and entered onto the Case Report Forms. Periodically, monitoring visits will be conducted 
and the Principal Investigator will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data. 
 
 


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12.0 
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13.0 
APPENDICES 
 
List of CYP3A4 active agents (substrates & inhibitors) 
 
13.1 
Appendix 1: Inhibitors of CYP3A4 
 
Amiodarone 
Anastrozole 
Azithromzcin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithyromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
 
Fluconazole 
Fluoxetine 
Fluvoaxamine 
Gestodene 
Grapefruit, Grapefruit juice 
Indinavir 
Isoniazid 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristine and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid 
 
 
13.2 
Appendix 2: Inducers of CYP3A4 
Barbiturates 
Bosentan 
Carbamazepine 
Efavirenz 
Glucocorticoids 
Modafinil 
 
Mitotane 
Nafcillin 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s wort 
Tipranavir/Ritonavir 
Troglitazone