Clinical Trial of a Rapidly Cycling, Non-Cross Reactive Regimen of Approved Therapeutic Agents to Treat Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Icahn School of Medicine at Mount Sinai

 
Clinical Trial of a Rapidly Cycling, Non-Cross Reactive Regimen of Approved Therapeutic Agents to Treat 
Prostate Cancer  
Dr. Bobby Liaw 
NCT02903160 
Document Date: 5-22-19 
 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
2 
Prostate Cancer Intensive, Non-Cross Reactive Therapy (PRINT) for CRPC 
 
Last Updated: 5/22/2019 
 
 
Principal Investigator: 
 
Bobby C. Liaw, MD 
Assistant Professor of Medicine, Division of Hematology and Medical Oncology 
Icahn School of Medicine at Mount Sinai  
Mount Sinai Downtown, Chelsea Center 
 
Co-Investigators: 
 
William K. Oh, MD 
Chief, Division of Hematology and Medical Oncology 
Deputy Director, Tisch Cancer Institute 
Professor of Medicine and Urology 
Ezra M. Greenspan, MD Professor in Clinical Cancer Therapeutics 
Icahn School of Medicine at Mount Sinai 
 
 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
3 
Synopsis 
 
Title:  
 
Prostate Cancer Intensive, Non-Cross Reactive Therapy (PRINT) for CRPC 
 
Study Schema: 
 
 
 
Objective:  
 
To evaluate the clinical benefit of using a rapidly cycling, non-cross reactive regimen of FDA-
approved prostate cancer therapeutic agents in treatment-naïve CRPC patients. 
 
Study Design: 
 
Investigator initiated study 
 
Single arm, prospective, open-label, non-randomized phase II clinical trial 
 
Enrollment at integrated Mount Sinai Health System  
 
Anticipated number of patients to be screened: 60 
 
Enrollment period: 3 years 
 
Follow up period: 2 years 
 
Primary Endpoint: 
 
Time to disease progression, either PSA or radiographic, after completion of all treatment 
modules 
 
Secondary Endpoints: 
 
Overall survival 
 
PSA response rate with each treatment module 
 
Alkaline phosphatase levels 
 
Safety 
 
Exploratory Endpoint: 
 
Correlation of a peripheral whole blood RNA signature with different treatment modalities and 
clinical outcome 
 
Changes to AR-V7 expression in CTCs with different treatment modalities and correlation with 
clinical outcome 
 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
4 
Inclusion Criteria: 
 
Histologically or cytologically confirmed adenocarcinoma of the prostate 
 
Metastatic castrate resistant prostate cancer, defined by progressive disease based on either 
rising PSA, new bone metastases, or progression of measurable disease on imaging, according to 
PCWG2 guidelines, despite androgen deprivation therapy 
 
Ongoing androgen deprivation therapy with a GnRH analogue, GnRH antagonist, or bilateral 
orchiectomy 
 
ECOG performance status 0–1 
 
Serum testosterone level < 50 ng/dL 
 
Absolute neutrophil count > 1,500/μL, platelet count > 100,000/μL, and hemoglobin > 9 g/dL 
 
Creatinine < 2 mg/dL 
 
Total bilirubin < 1.5 times the upper limit of normal, alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≤ 1.5 times the upper limit of normal 
 
Exclusion Criteria: 
 
History of uncontrolled seizure disorder 
 
Clinically significant cardiovascular disease including: 
o Myocardial infarction or uncontrolled angina within 6 months 
o Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients 
with history of congestive heart failure NYHA class 3 or 4 in the past 
o Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg 
or diastolic blood pressure > 105 mmHg at the screening visit 
 
Have used or plan to use from 30 days prior to enrollment through the end of the study 
medication known to lower the seizure threshold or prolong the QT interval 
 
Major surgery within 4 weeks of enrollment 
 
Radiation therapy within 4 weeks of enrollment 
 
Prior use of abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, carboplatin, or radium-
223 for the treatment of castration-resistant disease 
o Prior docetaxel use in the hormone-sensitive disease setting is allowed, but must be 
completed ≥ 4 weeks prior to enrollment 
o Prior sipuleucel-T use is allowed, but must be completed ≥ 4 weeks prior to enrollment 
o Concurrent use of zolendronic acid or denosumab is allowed on study 
 
Statistical Design: 
 
A sample size of 33 patients that complete all three treatment modules of the study regimen 
will provide 90% power for a one-sided test at the 5% level to detect an increase in median time 
to disease progression, either PSA or radiographic, from 3 months to 5 months.  We will plan to 
screen 60 patients (treat 40 patients) to account for any potential patient dropout, defined as 
anyone who does not complete all three treatment modules. 
 
 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
5 
1. Study Summary 
1.1 Background 
1.2 Research Proposal/Rationale 
2. Study Objectives 
2.1 Primary Objective 
2.2 Secondary Objectives 
2.2 Exploratory Objectives 
3. Study Design/Schema 
3.1 General Design 
3.2 Primary Study Endpoint 
3.2.1 PSA Progression 
3.2.2 Radiographic Progression 
3.3 Secondary Study Endpoints 
3.3.1 Overall Survival 
3.3.2 PSA Response 
3.3.3 Alkaline Phosphatase Levels 
3.3.4 Safety 
3.4 Exploratory Endpoints 
4. Study Design 
 
4.1 Eligibility 
 
 
4.1.1 Inclusion Criteria 
 
 
4.1.2 Exclusion Criteria 
4.2 Pretreatment Evaluation 
5. Drug Dosing and Rationale 
 
5.1 Anticipated Risks 
 
5.2 Adverse Events 
5.2.1 Definitions 
 
5.3 Management of Study Drug Events and Drug Dosing Modifications 
 
5.3.1 Abiraterone 
5.3.2 Radium-223 
5.3.2.1 NIST Standardization Amendment 
5.3.2.2 Dose calibration 
5.3.2.3 Dose calculation 
5.3.3 Cabazitaxel and Carboplatin 
5.3.3.1  Specific to Cabazitaxel 
5.3.4 Enzalutamide 
5.3.5 Prednisone 
5.4 Pharmacoviligance Specifications 
5.4.1 Sanofi - Obligations and Responsibilities of the IST/ISS Sponsor 
5.4.2 Sanofi Group Entity Pharmacovigilance 
5.4.3 Bayer - Obligations and Responsibilities of the IST/ISS Sponsor 
5.4.4 Bayer Global Pharmacovigilance Contact 
6. Follow Up, Laboratory Testing, and Diagnostic Imaging 
7. Statistical Plan 
8. Data Handling and Record Keeping 
8.1 Electronic Data Capture (EDC) System 
 
8.2 Verification of EDC System 
 
8.3 Entering data 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
6 
 
8.4 Data Validation Process 
 
8.5 Data Cleaning and Discrepancy Management 
 
8.6 Data Security 
 
8.7 Quality Control Procedures 
 
8.8 Medical and Adverse Event Coding 
8.9 Confidentiality 
8.10 Records Retention 
8.11 Subject Privacy 
9. Ethical Considerations 
10. Financial Considerations 
11. Publication Plan 
12. References 
 
 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
7 
List of Abbreviations 
 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ASCO 
American Society of Clinical Oncology 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CRPC 
Castration Resistant Prostate Cancer 
CT C/A/P 
Computed Tomography Scan of Chest, Abdomen, and Pelvis 
CTC 
Circulating Tumor Cell 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
mCRPC 
Metastatic Castration Resistant Prostate Cancer 
MRI 
Magnetic Resonance Imaging 
NIST 
National Institute of Standard and Technology 
PFS 
Progression Free Survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PSA 
Prostate Specific Antigen 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiographic Progression Free Survival 
RSI 
Reported Safety Information 
SRM 
Standard Reference Material 
TTP 
Time to Progression 
 
 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
8 
1. Study Summary 
 
1.1 Background 
Multiple new FDA approved therapies with different mechanisms of action are available for treatment 
of castration-resistant prostate cancer. 
Prostate cancer is the second most commonly diagnosed cancer, and the most common cause of cancer 
death in US males.  First line treatment of metastatic prostate cancer with androgen deprivation therapy 
(ADT) is effective in the majority of men, by significantly decreasing serum PSA levels and improving 
disease symptoms, but is not curative.  The disease eventually progresses despite ADT and becomes 
castration-resistant prostate cancer (CRPC).  Recent advances in understanding of prostate cancer 
biology and the androgen signaling axis has led to the development of multiple novel agents for 
treatment options for CRPC, each with its own distinct mechanism of action.  There are at least 4 
different classes of treatment recently FDA-approved for metastatic CRPC: androgen signaling inhibitors 
(abiraterone, enzalutamide), cytotoxic chemotherapy (cabazitaxel), immunotherapy (sipuleucel-T), and 
bone targeted therapy (radium-223).  Individually, each agent has demonstrated efficacy and survival 
benefits in randomized, phase III clinical trials [1-7]. 
 
The standard approach is to use one treatment until resistance develops, then change to a different 
treatment. 
While optimal timing and sequence of these new treatments are still the subject of clinical investigation, 
the standard treatment approach so far has been to continue with a single treatment agent until 
resistance develops, at which point the patient is switched to a different treatment. 
The emerging concept of tumor heterogeneity, both between different prostate cancer patients and 
within a single tumor, argues that a “one size fits all” sequential, single-agent approach to cancer 
treatment ultimately will have limited success.  Inherent genetic instability from rapidly dividing 
malignant cells can lead to substantial tumor heterogeneity [8], and along with it, varied amounts of 
genetic dysregulation and varied patterns of anti-neoplastic resistance [9].  A single agent treatment 
may succeed in effecting a response on the majority of malignant cells, but may select for more resilient 
subpopulations, eventually leading to drug resistance and treatment failure.  New first-in-class 
therapeutics that exhibit anti-tumor activity even in the face of multi-drug resistance are in 
development, but eventually these will likely breed resistance as well. 
 
Combining drugs is a classic oncologic paradigm, but dose limiting toxicities can be significant. 
Combination drug therapy has been a paradigmatic approach not only to improve response to 
treatment, but also to avoid therapeutic resistance.  The probability of the disease simultaneous 
developing resistance towards multiple agents is far less than that towards a single agent alone.  This 
concept has parallels in treatment of infectious disease, where the simultaneous use of multiple 
antibacterial or antiretroviral agents has long been the standard for treatment of tuberculosis and HIV, 
respectively.  Multiple regimens of combination chemotherapy are already in routine use in both the 
hematologic and solid tumor malignancies, with significant rates of cures in diseases such as Hodgkin 
lymphoma and testicular cancer.   
 
Treating prostate cancer simultaneously with multiple agents from each class of therapy (androgen 
signaling inhibitors, cytotoxic chemotherapy, immunotherapy, bone-targeted therapy) would cause 
significantly increased side effects.  While it may be more justifiable to treat with a regimen that has 
more side effects when the intent is curative, regimens meant to control or palliate a malignancy over 
longer periods of time need to strike a fine balance between toxicity, efficacy, and quality of life.   

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
9 
Overlapping toxicities of non-cross reactive treatment drugs and their supportive regimens would make 
delivering each drug at its respective optimal therapeutic dosing and schedule a difficult task, and would 
limit therapeutic impact. 
 
New drug deployment strategies are needed to address this issue.  Metastatic CRPC patients offer a 
unique opportunity to establish an optimal sequence of treatment as this has not yet been 
accomplished with these many recently approved agents. 
 
Rapid cycling of therapy allows targeting of different cell populations, switching to non-cross reactive 
therapies before development of resistance and the potential to increase long term disease control. 
One solution to minimize toxicity and mimic the benefits of multidrug combination treatment is to 
rapidly cycle therapies, maintaining the end goal of exposing the disease to multiple agents in a 
relatively short duration of time.  This is a concept already in clinical use, and hard-wired into some 
standard-of-care chemotherapy regimens, particularly in the treatment of aggressive hematologic 
malignancies.  Hyper-CVAD, used in the treatment of acute lymphocytic leukemia (ALL) [10] and Burkitt 
lymphoma [11], and the Stanford V regimen, used in advanced bulky Hodgkin lymphoma [12], are two 
examples of complex regimens that require alternating cycles of different drug combinations.  They rely 
on the differential timing and delivery of different drugs to be able to preserve dose intensity of each 
individual agent, without being overwhelming by toxicities. 
 
Understanding that metastatic prostate cancer is a heterogeneous disease [13-15], both intrapersonally 
and between patients, the cycling of treatment would allow for the targeting of different cell 
populations.  By switching between non-cross reactive therapies, the selective pressure exerted by any 
one therapeutic agent’s intermittent use is limited [16], allowing resistance rates to stabilize or decrease 
in its absence.  The rationale underlying this strategy is that drug resistance evolution is related to the 
duration of drug exposure, and that a gain of drug resistance comes with a biological fitness cost.  This is 
a concept also seen in infectious diseases; the higher the fitness cost, the more rapidly the resistance 
frequency fades in a disease population once the selective pressure is removed, as the nonresistant cells 
outcompete the resistant cells [17].  In this way, the same agent can be reintroduced at a later time with 
its efficacy intact, sustaining drug sensitivity and long term disease response. 
 
1.2 Research Proposal/Rationale 
This phase II clinical trial will explore the efficacy of rapidly cycling non-cross reactive treatment 
therapies in the treatment of patients with newly diagnosed mCRPC.  The primary hypothesis is that the 
best chance of eliminating or controlling disease is when the cancer is treatment naïve, and has not yet 
developed therapeutic resistance.  By finding an optimal drug deployment strategy of already approved 
and available treatments for mCRPC, we believe we can more effectively treat an intrinsically 
heterogeneous disease, delay/prevent drug resistance, as well as minimize treatment toxicity. 
 
All of the treatment agents selected have well-defined individual toxicity profiles from large phase III 
trials, but there is limited clinical data about the toxicity profiles of these drugs in combinations.  While 
each agent is generally well tolerated, toxicities remain a significant concern given the older age of the 
typical mCRPC patient, the comorbid conditions common to this patient population, as well as those 
borne from previous chronic androgen deprivation therapy.   
 
Each drug in the proposed treatment regimen will be used at their FDA-approved dosing and indication, 
with the exception of cabazitaxel, which will be used prior to disease demonstration of docetaxel failure, 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
10
and in combination with carboplatin (discussed below).  The proposed sequencing is rationally designed, 
and based on each drug’s distinct mechanisms of action as well as their toxicity profiles.   
 
Our rapidly-cycling treatment regimen contains three, separate, consecutive treatment modules, each 
lasting 3 months: 1. Abiraterone; 2. Cabazitaxel + Carboplatin; 3. Enzalutamide + Radium-223.  
Therapeutic agents are delivered as non-cross reactive combinations, in order to achieve optimal 
therapeutic dosing at each cycle and decrease possibility of significant adverse effects. 
 
Utilizing PCWG2 guidelines to define progression of disease by PSA levels, a patient must have been on 
treatment for at least 12 weeks, which coincides with the duration of one of our treatment modules.  As 
designed into our trial, CT and bone scans will be obtained every 12 weeks, making the earliest possible 
determination of radiographic disease progression also 12 weeks.  The design of the treatment schedule 
is such that the treatment modality will be changed regardless of the type of response observed at the 
end of each module.  For patients progressing on a previous treatment module, they are already pre-
planned to transition to a different treatment agent, which is in line with standard of care management 
of mCRPC.  In this way, we anticipate minimal patient dropout from a disease progression standpoint. 
 
Sipuleucel-T will not be given as part of the treatment protocol, but prior sipuleucel-T use will be 
allowed for participants of this clinical trial.  We will track its use in our cohort of patients.  The rationale 
for allowing previous administration of sipuleucel-T is based on the understanding that immunotherapy 
requires time to build host immune sensitivity, and likely works best on low disease burden [18].  As 
sipuleucel-T is approved for use only in the asymptomatic or minimally symptomatic stages of disease, 
this would grant patients the opportunity to receive a treatment that has shown overall survival benefit 
in large, randomized phase III clinical trial.  It would also allow patients to receive it at a time before they 
have had any significant corticosteroid exposure, which the majority of other CRPC treatments require, 
as it may blunt immunologic effects of dendritic cell vaccines. 
 
In keeping with standard of care, concurrent zolendronic acid or denosumab use will be allowed on 
study, we will track its use in our cohort of patients 
 
Controlling the androgen signaling axis remains key in CRPC, but there exists heterogeneity in response 
and progression to drugs which target this pathway in prostate cancer.  A comprehensive approach to 
targeting the androgen signaling axis via androgen synthesis inhibition and androgen receptor blockade 
will be undertaken with abiraterone and enzalutamide.  Both therapeutic agents have been approved by 
the FDA for treatment of mCRPC in both the pre-chemotherapy and post-chemotherapy space based on 
their merits in prolonging time to PSA progression and PFS in chemotherapy-naïve patients [3, 19], and 
OS benefits in the chemotherapy-refractory patients [2, 4]. 
 
While no directly comparative studies have been performed, both abiraterone and enzalutamide 
showed in their respective randomized trials to have comparable median time to PSA progression (11.1 
months and 11.2 months) in the pre-chemotherapy setting.  Optimal sequencing of the two AR-pathway 
targeting agents have been the subject of controversy, especially as there are likely overlapping 
mechanisms of resistance between abiraterone and enzalutamide [20-23].  Small studies looking at the 
efficacy of one agent following the other in direct sequence suggest that the percentage of men who 
have a >50% PSA response from the later agent are higher in those who received abiraterone first and 
enzalutamide second [20-24].  The role of glucocorticoid receptors as a potential mechanism of 
enzalutamide resistance [25] also lends consideration for sequencing abiraterone earlier given its 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
11
requirement for concurrent prednisone.  With this data in mind, we have sequenced abiraterone to be 
given first in the rapidly cycling regimen, to be followed by enzalutamide at a slightly later time. 
 
Sequencing a second androgen pathway inhibitor following failure of a previous one is not strongly 
supported because of likely overlapping mechanisms of resistance.   Earlier studies raise the possibility 
of cross-resistance between AR-directed agents and taxanes [26], specifically the decreased efficacy of 
docetaxel in abiraterone-refractory mCRPC [27].  Mechanistically, it’s hypothesized that taxanes disrupt 
microtubule function, which is essential not only in cellular division, but also in androgen receptor 
nuclear trafficking [28].  More recent data suggests that taxanes exhibit their significant antineoplastic 
effects through AR-pathway independent pathways as well, with second generation agents such as 
cabazitaxel retaining efficacy even in the enzalutamide-refractory setting [29].  In keeping with our 
underlying principle to cycle treatments with different mechanisms of action in order to avoid 
development of resistance, the cytotoxic chemotherapy module is juxtaposed between the abiraterone 
and enzalutamide modules. 
 
Though structurally similar, recent in vitro data finds that cabazitaxel suppresses microtubule dynamic 
instability more strongly than docetaxel, is taken up into cells significantly faster, and is retained in cells 
longer, likely explaining the potency of cabazitaxel in docetaxel-resistant tumors [30].  Given that this 
trial is designed to thwart resistance development, this drives the decision to move cabazitaxel into a 
position of front-line therapy.  A phase III randomized trial is currently underway to compare 
cabazitaxel/prednisone vs. docetaxel/prednisone in the chemotherapy-naïve CRPC population 
(NCT01308567).   
 
Platinum agents have long been studied in prostate cancer and may play a stronger role in treatment of 
prostate cancer with neuroendocrine or aggressive features.  Androgen-independent neuroendocrine 
cells, which are classically platinum-sensitive, are thought to be selected for by prolonged courses of 
androgen deprivation [31].  Recent studies have shown that the addition of carboplatin to docetaxel is 
well tolerated and demonstrates significant activity both in the first-line and the docetaxel-refractory 
disease setting [32-34]. 
 
While the combination of cabazitaxel and carboplatin have not yet been extensively studied, side effect 
profiles between docetaxel and cabazitaxel are similar given their similar mechanisms of action, making 
it a suitable and reasonable substitute for docetaxel.  A phase I study of the cabazitaxel and carboplatin 
combination finds it to be safe and have significant antitumor activity [35], with its key dose-limiting 
toxicity of neutropenia able to be abrogated with the addition of pegfilgrastim.  Recently reported at 
ASCO 2015, a multi-institutional randomized phase II study comparing cabazitaxel vs. cabazitaxel plus 
carboplatin demonstrated improved PFS and response rates with the addition of carboplatin to 
cabazitaxel in men with mCRPC that have failed at least one line of prior therapy [36]. 
 
Radium-223 dichloride has a modest toxicity profile, and is not anticipated to have significant 
interactions or overlapping toxicities with enzalutamide.  It will only be given to patients with bone 
metastases demonstrated on imaging in accordance with its well-delineated mechanism of action.  The 
presence of visceral metastases will not discount the use of radium-223, as it will be paired with 
enzalutamide. 
 
Radium-223 will not be offered in combination with abiraterone as part of this study, due to a recent 
safety analysis leading to the unblinding of a randomized trial evaluating abiraterone with or without 
radium (NCT02043678).  Interim data suggests an increased treatment emergent fractures, worse 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
12
symptomatic skeletal events-free survival, and more total deaths in the abiraterone plus radium-223 
treatment arm. 
 
As CRPC is a heterogeneous disease with varied prognosis, biomarker development has been a field of 
great clinical interest and active development.  Tracking changes in prostate cancer over time is 
challenging due to the need for rebiopsy in order to obtain fresh tissue.  Blood-based biomarker assays 
are far less invasive and easier to incorporate into clinical practice. 
 
Peripheral blood cell gene expression is altered by interactions with its environment, including 
neoplastic tissue.  The transcriptional profiling of whole blood has the potential to capture underlying 
biological and immunological processes that drive prostate cancer, and can yield crucial prognostic 
information in men with CRPC.  We previously developed a six-gene RNA signature (consisting of ABL2, 
SEMA4D, ITGAL, C1QA, TIMP1, and CKDN1A) with prognostic significance for survival, demonstrating the 
ability to stratify men with CRPC into low-risk and high-risk groups [37].  The effect of different classes of 
therapeutic agents on this six gene signature, as well as its correlation with clinical outcome, is the 
subject of further study.   
 
A potential mechanism by which CRPC gains resistance to AR-directed agents is via constitutively active 
androgen receptor variants (AR-V).  AR-Vs have been shown to be expressed in hormone-sensitive 
prostate cancer cells, but at significantly lower levels as compared to castration-resistant disease [38].  
Recent data associates patients with AR-V7 expression in circulating tumor cells (CTCs) with worse 
treatment response to AR-target agents [39], suggesting AR-V7 as a predictive biomarker for resistance.  
More studies are needed to validate AR-V7 as a predictive biomarker, as well as to better understand 
changes to its expression associated with different therapeutic agents and clinical outcome. 
 
The design of this trial will expose patients to multiple different types of therapy and have a significant 
interval of follow up, so it presents a prime opportunity to evaluate the predictive potentials of the six-
gene signature and AR-V7 expression.  We also plan to bank additional blood specimens for future 
correlative science studies. 
 
2. Study Objectives 
To our knowledge, no study has evaluated the use of rapidly cycling, non-cross reactive therapies for the 
treatment of mCRPC.  Our hypothesis is that the identification of optimal combinations and sequencing 
of rapidly cycling non-cross reactive therapies can help prevent or delay the development of therapeutic 
drug resistance, and can be safely tolerated. 
 
2.1 Primary Objective 
The primary objective of the study is: 
 
To evaluate time to disease progression, as determined by either PSA or radiographic 
progression, after completion of all modules of the rapidly-cycling, non-cross reactive regimen in 
patients with mCRPC. 
 
2.2 Secondary Objectives 
The secondary objectives are: 
 
To evaluate overall survival 
 
To assess PSA response rate with each treatment module  
 
To assess changes to alkaline phosphatase levels 
 
To assess safety of the rapidly-cycling, non-cross reactive regimen 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
13
 
2.3 Exploratory Objectives 
The exploratory objective are: 
 
To evaluate the correlation of a peripheral whole-blood RNA signature with clinical outcome 
measures during and after treatment. 
 
To evaluate changes to AR-V7 expression in CTCs with different treatment modalities and clinical 
outcomes. 
 
3. Study Design/Schema 
 
 
3.1 General Design 
This is a prospective open-label non-randomized phase II clinical trial of rapidly cycling non-cross 
reactive prostate cancer treatments in patients with treatment-naïve metastatic CRPC.  Treatments will 
include enzalutamide, cabazitaxel, carboplatin, abiraterone, and radium-223.  Radium-223 will only be 
given to patients with known bone metastases.  Expected duration of subject participation is 24 months. 
 
3.2 Primary Study Endpoint 
The primary clinical endpoint of this study is the time to disease progression after completion of all 3 
modules of the rapidly-cycling study regimen.  Disease progression is determined by either PSA or 
radiographic progression, whichever occurs first.  Only disease progression that occur after the 
completion of all treatment modules will be counted. 
 
3.2.1 PSA Progression 
PSA progression is as defined by PCWG2 criteria [40].  Baseline PSA will be defined as the serum PSA 
level measured following completion of the third treatment module.   
 
PSA changes will be reported globally using a waterfall plot for each module.  In patients who have a 
decline in PSA value from baseline, progression is defined by: 
 
An increase in PSA by 25% above the nadir, AND 
 
An increase in PSA by a minimum of 2 ng/ml, or an increase in PSA to the pre-treatment PSA 
value, AND 
 
Confirmation by a second PSA at least 3 weeks apart, AND 
 
Occur following at least 12 weeks of therapy, AND 
 
There is no objective evidence of disease response. 
 
In patients whose PSA value from baseline has not declined from baseline, progression is defined by: 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
14
 
An increase in PSA by 25% above either the pre-treatment level, or the nadir PSA level 
(whichever is lowest), AND 
 
An increase in PSA by a minimum of 2 ng/ml, AND 
 
Confirmation by a second PSA at least 3 weeks apart, AND 
 
Occur following at least 12 weeks of therapy, AND 
 
There is no objective evidence of disease response. 
 
3.2.2 Radiographic Progression 
Radiographic progression will be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 criteria, with definitions of CR, PR, SD, and PD for target and non-target lesions as defined 
below.  Baseline imaging defined as the CT and bone scan obtained following completion of the third 
treatment module.   
 
Lesions are categorized as either measurable or non-measurable based on the criteria below.  All 
measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 6 weeks before the beginning of the treatment.  Tumor lesions that are situated in a previously 
irradiated area will not be considered measurable. 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 
 
Guidelines for Evaluation of Measurable Disease 
Conventional CT and MRI - These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and neck tumors and those of 
extremities usually require specific protocols. 
 
Categorization of Radiologic Lesions 
Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) with a minimum size of 10 mm by CT scan (CT scan slice thickness no 
greater than 5 mm) and 20 mm by conventional techniques (X-ray).  All tumor measurements will be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis 
when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis of the lymph nodes will be measured and followed. 
 
Non-Measurable Disease 
All other lesions, including small lesions (longest diameter <10 mm on CT or pathological lymph nodes > 
10 to <15 mm in short axis) as well as truly non-measurable lesions. Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
 
 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
15
Special considerations  
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone 
lesions. However, these techniques can be used to confirm the presence or disappearance of bone 
lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
 
Target Lesions 
All measurable lesions up to a maximum of 5 lesions per organ and 10 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 
longest diameters (LD) for all target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as reference by which to characterize objective tumor response. 
 
Non-Target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.  Non-target lesions include measurable lesions that exceed the maximum numbers 
per organ or total of all involved organs as well as non-measurable lesions. Measurements of these 
lesions are not required, but the presence or absence of each should be noted throughout follow-up. 
 
Response Criteria for Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, 
taking as reference the baseline sum LD. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started.  The sum must also demonstrate 
an absolute increase of at least 5 mm.  The appearance of one or more new lesions is also considered 
progression. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since the treatment started. 
 
Response Criteria for Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of two or more new lesions and/or unequivocal progression of 
existing non-target lesions. 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
16
 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail, and the progression status should be confirmed at a 
later time by the Principal Investigator. 
 
Outcomes Based on Radionuclide Bone Scans 
The subjectivity in interpreting serial changes in radionuclide bone scan is well recognized.  The primary 
outcome will be whether the scan is stable or improved vs. worse or progression.  Changes in intensity 
will not be used as an outcome measure.   
 
Stable/Improved: A stable or improved classification requires that no new lesions appear or that new 
pain has not developed in an area that was previously visualized. 
 
Progression: Two or more new lesions not consistent with tumor flare, confirmed on a second bone scan 
≥ 6 weeks later that shows ≥ 1 additional new lesion. 
 
 
3.3 Secondary Study Endpoints 
Secondary end points include evaluation of overall survival, PSA response to each treatment module, 
alkaline phosphatase response to each module, and safety.   
 
3.3.1 Overall Survival 
Overall survival will be defined as the time of study entry to death from any cause.   
 
3.3.2 PSA Response 
PSA response rates to the overall regimen as well as to each individual treatment module will be 
evaluated.  For the purposes of calculating PSA response for the overall regimen, baseline PSA level will 
be defined as the PSA drawn at day 0.  For calculating PSA response for individual treatment modules, 
baseline PSA will be defined as the PSA drawn at the beginning of that treatment module.  Patients who 
do not tolerate at least 12 weeks of therapy will not be evaluable for PSA response. 
 
Patients with a 50% PSA decline from their baseline PSA level will be considered responders, provided 
objective tumor measurements are stable or also demonstrate response.  Patients with a 25% PSA 
increase from their baseline PSA will be considered nonresponders.  Patients that do not meet criteria 
for responder or nonresponder, will be considered to have stable disease. 
 
3.3.3 Alkaline Phosphatase Levels 
Serum alkaline phosphatase levels will be monitored throughout the rapidly-cycling treatment regimen.  
Changes to alkaline phosphatase levels will be assessed at the end of each individual treatment module, 
upon completion of the rapidly-cycling treatment regimen, and at time of disease progression. 
Although alkaline phosphatase is a relatively nonspecific biomarker, the dominant source of alkaline 
phosphatase in patients with bone metastases is likely from the bone, and may reflect volume of bony 
metastatic disease and rate of bone turnover. 
 
3.3.4 Safety 
Throughout the study, safety and tolerability of the rapidly cycling non-cross reactive multi-drug 
treatment regimen will be assessed by the recording of adverse events, monitoring of vital signs and 
physical examinations, safety laboratory evaluations, and 12-lead ECG. 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
17
 
3.4 Exploratory Endpoints 
We will evaluate whether there are prognostic or predictive implications associated with changes in the 
whole blood six-gene RNA signature score with each treatment module, clinical response to treatment, 
and overall clinical outcome. 
 
AR-V7 expression in CTCs will be evaluated serially throughout the treatment period and post-treatment 
observation period for a subset of the study patients.  Changes to AR-V7 expression will be monitored 
with each treatment module, clinical response to treatment, overall clinical outcome, and at time of 
disease progression.   
 
Additional blood specimens will be banked for future correlative science studies. 
 
4. Study Design 
This single-arm phase II study will enroll patients over a 36 month period from the Mount Sinai Health 
System.  We anticipate the enrollment of 2-3 patients per month to the clinical trial.  Patients will be 
followed for at least 24 months following the last patient’s entry. 
 
4.1 Eligibility 
 
4.1.1 Inclusion Criteria 
Patients must meet the following inclusion criteria: 
 
Histologically or cytologically confirmed adenocarcinoma of the prostate 
 
Metastatic castrate resistant prostate cancer, defined by progressive disease based on either 
rising PSA, new bone metastases, or progression of measurable disease on imaging, according to 
PCWG2 guidelines, despite androgen deprivation therapy 
 
Ongoing androgen deprivation therapy with a GnRH analogue, GnRH antagonist, or bilateral 
orchiectomy 
 
ECOG performance status 0–1 
 
Serum testosterone level < 50 ng/dL 
 
Absolute neutrophil count > 1,500/μL, platelet count > 100,000/μL, and hemoglobin > 9 g/dL 
 
Creatinine < 2 mg/dL 
 
Total bilirubin < 1.5 times the upper limit of normal, alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≤ 1.5 times the upper limit of normal 
 
4.1.2 Exclusion Criteria 
Patients must not meet any of the following exclusion criteria: 
 
History of uncontrolled seizure disorder 
 
Clinically significant cardiovascular disease including: 
o Myocardial infarction or uncontrolled angina within 6 months 
o Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients 
with history of congestive heart failure NYHA class 3 or 4 in the past 
o Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg 
or diastolic blood pressure > 105 mmHg at the screening visit 
 
Have used or plan to use from 30 days prior to enrollment through the end of the study 
medication known to lower the seizure threshold or prolong the QT interval 
 
Major surgery within 4 weeks of enrollment 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
18
 
Radiation therapy within 4 weeks of enrollment 
 
Prior use of abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, carboplatin, or radium-
223 for the treatment of castration-resistant disease.   
o Prior docetaxel use in the hormone-sensitive disease setting is allowed, but must be 
completed ≥ 4 weeks prior to enrollment 
o Prior sipuleucel-T use is allowed, but must be completed ≥ 4 weeks prior to enrollment 
o Concurrent use of zolendronic acid or denosumab is allowed on study 
 
4.2 Pretreatment Evaluation 
All patients must sign a written informed consent form before study specific screening procedures are 
performed.  Informed consents may be obtained up to 30 days prior to day 1 of treatment.  Screening 
procedures to evaluate patient eligibility for the study will be conducted within 8 weeks prior to day 1.  
The pretreatment evaluation includes a complete medical history and physical examination.  Baseline 
studies include complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), 
lactate dehydrogenase (LDH), PSA, and testosterone panel.  Baseline EKG, bone scan, and CT 
chest/abdomen/pelvis will also be performed up to 8 weeks prior to Day 1 of treatment.    
 
If baseline CT and bone scan are without radiographic evidence of metastatic disease, but metastatic 
disease is demonstrated on newer imaging modalities that are more sensitive and specific for prostate 
cancer, such as F18-fluciclovine PET scan or Ga68-PSMA PET scan, these patients will be considered 
eligible for the study.   
 
If the patient meets eligibility, they will return on Day 1 to be initiated on the first treatment module of 
the clinical trial. 
 
 
5. Drug Dosing and Rationale 
The proposed dosing for abiraterone, cabazitaxel, enzalutamide, and radium-223 are that which the FDA 
has approved them for.  Each of these agents has been studied in individual large, multi-center phase III 
trials in men with mCRPC, and have demonstrated benefits in OS, and either PFS or TTP [1-4, 6].  As per  
FDA approved indication, radium-223 will only be given to patients with known bone metastases 
demonstrated on radiographic imaging.  Abiraterone acetate must be taken on an empty stomach (one 
hour before or two hours after food) as systemic exposure of abiraterone acetate is increased by 5- and 
10-fold when administered with a low- and high-fat meals, respectively, as compared to overnight 
fasting.    
 
 
The combination of cabazitaxel and carboplatin is not a standard treatment regimen for mCRPC, but is 
under active investigation.  A phase I study presented at GU ASCO 2014 finds the combination of 
cabazitaxel, dosed at 25 mg/m2 (FDA approved dosing), and carboplatin, at AUC 4, to be safe and have 
significant antitumor activity.  The use of supportive pegfilgastim mitigates neutropenia, which is the key 
dose-limiting toxicity of cabazitaxel [35].  Premedication, consisting of a single intravenous dose of an 
antihistamine, histamine H2-antagonist (except cimetidine), and corticosteroids (dexamethasone 12 mg 
or equivalent), should be administered 30 minutes or more before cabazitaxel.  Antiemetic prophylaxis 
can be given at the physician’s discretion.  Recent phase III study, PROSELICA, shows noninferiority of 20 
mg/m2 dosing as compared to 25 mg/m2 dosing, leading to this study adopting the lower dose in order 
to limit myelosuppression [41].  To enhance efficacy, cabazitaxel will be administered before carboplatin 
[42]. 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
19
 
Each treatment module will last 12 weeks.  Oral agents will be started on day 1 of each module and be 
continued at home on a daily basis until day 72.  For intravenous treatments, aa total of 4 cycles are 
planned for cabazitaxel and carboplatin, and a total of 3 doses of radium-223 in patients with known 
bone metastases.   
Study visits and intravenous treatments should adhere as closely to the schedule as possible, but a 
deviation from schedule of ± 5 days will be allowed.  Reasonable deviations from schedule will also be 
made for holidays and religious observances. 
 
The table below lists each therapeutic agent, dosing, and associated supportive regimens.   
 
Treatment Module 
Therapeutic Agent 
Dosing 
Supportive Regimen 
1 
Abiraterone 
1000 mg PO once 
daily one hour 
before or two hours 
after food 
Prednisone 5 mg PO BID 
2 
Cabazitaxel 
20 mg/m2 IV on D1, 
every 3 weeks 
Prednisone 5 mg PO BID; 
Pegfilgastim 6 mg SQ, 24-
72 hours after completion 
of each cabazitaxel cycle; 
Antiemetics as needed 
Carboplatin 
AUC 4 IV on D1, 
every 3 weeks 
None 
3 
Enzalutamide 
160 mg PO once 
daily 
None 
Radium-223 
50 kBq/kg IV on D1, 
every 4 weeks (55 
KBq after 
implementation of 
NIST update) 
None 
 
 
Module 1** 
(12 weeks) 
Module 2** 
(12 weeks) 
Module 3** 
(12 weeks) 
D1 
D29 D57 D1 
D2 
D22 D23 D43 D44 D64 D65 D1 
D29 D57 
Abiraterone 
daily 
 
 
 
 
 
 
 
 
 
 
 
Prednisone 
daily 
 
 
 
 
 
 
 
 
 
 
 
Cabazitaxel 
 
 
 
x 
 
x 
 
x 
 
x 
 
 
 
 
Carboplatin 
 
 
 
x 
 
x 
 
x 
 
x 
 
 
 
 
Pegfilgrastim 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
 
 
Prednisone 
 
 
 
daily 
 
 
 
Enzalutamide 
 
 
 
 
 
 
 
 
 
 
 
daily 
Radium-223* 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
* only in patients with known bone metastases 
** deviation from schedule of ± 5 days allowed for study visits and IV therapies 
 
5.1 Anticipated Risks 
The adverse effect profiles of each therapeutic agent in the proposed treatment regimen have been well 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
20
studied in large clinical trials.  The Reported Safety Information (RSI) for expectedness of adverse events 
for this study are detailed by each drug’s respective package insert.   
 
Concurrent participation in another clinical trial or treatment with any other anti-cancer therapy is not 
permitted. The Investigator may prescribe any other concomitant medications as deemed necessary. 
 
Abiraterone 
Abiraterone is generally well tolerated, as demonstrated by two large phase III trials, in both the pre- 
and post-chemotherapy settings [2, 3].  Compared to placebo, abiraterone has a notably higher 
incidence of adverse effects associated with mineralocorticoid excess due to CYP17 blockade: fluid 
retention/edema, hypokalemia, and hypertension.  These side effects are generally grade 1 or 2, and are 
mitigated by the addition of low dose prednisone.  Cardiac disorders and LFT abnormalities also occur at 
a slightly higher incidence with abiraterone than with placebo, although without significant increases in 
fatal cardiac or hepatic events.  Hepatotoxicity consists primarily of a reversible elevation in 
aminotransferase levels.  The most common side effects observed with abiraterone are fatigue, back 
pain, nausea, constipation, bone pain, and arthralgia, and are primarily grade 1 or 2.  Dose 
modification/interruption or treatment discontinuation of abiraterone due to adverse effects was 
similar to that of placebo in both phase III trials. 
 
Radium-223 
As radium-223 is a highly targeted radioisotope with short range effects, adverse effects to normal 
tissue and myelosuppression is minimized.  Overall incidence of adverse events of all grades, and those 
graded III or IV, were lower in the radium-223 arm as compared to the placebo arm in the phase III trial 
that got it approved [6].  Notable grade 3 and 4 adverse events associated with radium-223 include 
disease progression, bone pain, anemia, and spinal cord compression.  No differences in the frequency 
of hematologic toxicities were observed between the radium and placebo arms.  One instance of grade 
5 thrombocytopenia occurred during the trial that is considered possibly due to radium-223. 
 
Cabazitaxel 
In phase III study [1], cabazitaxel commonly caused hematological toxicities, of which the most common 
grade 3 or higher adverse events were neutropenia, leukopenia, and anemia.   Common grade 3 or 
higher non-hematologic toxicities include diarrhea, fatigue, and asthenia.  The diarrhea was expectantly 
managed.  Peripheral neuropathy, a notable side effect of the taxane class, was present in 14% of 
patients in the cabazitaxel arm, although was uncommon (1%) as a grade 3 or higher adverse event.  
 
The combination of cabazitaxel and carboplatin have been demonstrated to be safe when given 
concurrently; its key dose-limiting toxicity of neutropenia abrogated with the administration of 
prophylactic pegfilgrastim [35], which this trial incorporates.  Notable grade 3-4 adverse events of the 
cabazitaxel/carboplatin combination reported by a recent randomized phase II study were mainly 
hematologic: neutropenia (15%), anemia (10%), thrombocytopenia (8%), and fatigue (10%).  Febrile 
neutropenia was a rare occurrence (2%) [36]. 
 
Carboplatin 
Carboplatin is a well studied agent and used in multiple chemotherapy combinations.   Dosing is 
calculated by the target AUC using the Calvert formula: total dose (in milligrams) = Target AUC x (GFR + 
25).  For GFR that is estimated instead of measured, the FDA recommends capping GFR at a maximum of 
125 mL/min to avoid potential toxicities.  Its most notable adverse effects are hematologic: moderate 
incidence of grade 3/4 anemia (21%), leukopenia (15-26%), neutropenia (16-21%), and 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
21
thrombocytopenia (25-35%).  Myelosuppression is dose dependent and is often the dose limiting 
toxicity.  Other commonly reported adverse effects of carboplatin include pain, nausea, vomiting, 
weakness, hypersensitivity/allergic reactions, electrolyte disturbances (hyponatremia, 
hypomagnesemia, hypocalcemia, hypokalemia), decreased creatinine clearance, and LFT abnormalities.  
Carboplatin has limited nephrotoxic and ototoxic potential.  
 
Enzalutamide 
Enzalutamide, when used prior to chemotherapy exposure, was shown to have a good tolerability 
profile in PREVAIL [19], having similar rates of grade 3 or higher adverse events as compared to placebo 
(43% vs. 37%).  Adverse events that occurred slightly more often with enzalutamide include fatigue (36% 
vs. 26%), back pain (27% vs. 22%), constipation (22% vs. 17%), and arthralgia (20% vs. 16%), although 
the majority of these are grade 1 or 2 in severity.  Seizure was reported in 2 patients in the PREVAIL 
study, with one in each the treatment and placebo arms. 
 
5.2 Adverse Events 
An adverse event or experience is defined as any symptom, sign, illness, or untoward experience 
(including a clinically significant laboratory finding classified as grade ≥ 3 by the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events [CTCAE]) that develops or worsens during 
the course of the study, whether or not the event is considered related to study drug, and should be 
recorded only after the first dose of study drug is taken.  Serious adverse events are recorded from the 
time the informed consent form is signed. 
 
5.2.1 Definitions 
Serious adverse event (SAE): any untoward medical occurrence that at any dose:  
 
Results in death, 
 
Is life threatening, (Note: the term “life-threatening” refers to an event/reaction in which the 
patient was at risk of death at the time of the event/reaction; it does not refer to an event/ 
reaction which hypothetically might have caused death if it were more severe), 
 
Requires inpatient hospitalization or results in prolongation of existing hospitalization, 
 
Results in persistent or significant disability/incapacity, 
 
Is a congenital anomaly/birth defect, or 
 
Is a medically important event or reaction. Medical and scientific judgment should be exercised 
in deciding whether other situations should be considered serious, such as important medical 
events that might not be immediately life-threatening or result in death or hospitalization, but 
might jeopardize the patient or might require intervention to prevent one of the other 
outcomes listed in the definition above. 
 
Related Adverse Event, i.e. Adverse Drug Reaction (ADR): There is a reasonable possibility according to 
the IST/ISS sponsor that the product may have caused the event. 
 
Unexpected Adverse Drug Reaction: An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g., package insert/summary of product 
characteristics for an approved product). An expected ADR with a fatal outcome should be considered 
unexpected unless the local/regional product labeling specifically states that the ADR might be 
associated with a fatal outcome. 
 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
22
5.3 Management of Study Drug Events and Drug Dosing Modifications 
The Reported Safety Information (RSI) for expectedness of adverse events for this study are detailed by 
each drug’s respective package insert. 
 
Concurrent participation in another clinical trial or treatment with any other anti-cancer therapy is not 
permitted. The Investigator may prescribe any other concomitant medications as deemed necessary. 
 
5.3.1 Abiraterone 
For a grade 3 or higher adverse event associated with abiraterone, a maximum of 2 dosage reductions 
will be allowed.  At each dose reduction, the total dose will be decreased by 250 mg.  Specific AE’s and 
their management strategies are specified below.  Any return to protocol dose level after dose reduction 
must follow documentation of AE resolution and a discussion with the Primary Investigator. 
 
Adverse Event 
Action 
Further Action and/or Maintenance 
Hypokalemia ≥ 
Grade 3 
 
Hold abiraterone and initiate IV K+ 
and cardiac monitoring. 
 
Reinitiating abiraterone at either full 
or reduced dosage requires 
discussion with Primary Investigator. 
Hypertension ≥ 
Grade 3 
 
Hold abiraterone, blood pressure 
management with antihypertensives. 
 
Once resolved to ≤ Grade 1, reinitiate 
abiraterone at full dose. 
 
If toxicity recurs, hold abiraterone 
until resolved to ≤ Grade 1, and 
reinitiate at reduced dose of 750 mg 
daily. 
 
If toxicity recurs despite first dose 
reduction, hold abiraterone until 
resolved to ≤ Grade 1, and reinitiate 
at a further reduced dose of 500 mg 
daily. 
 
If toxicity recurs despite second dose 
reduction and optimal hypertension 
management, discontinue 
abiraterone. 
Edema ≥ Grade 3 
 
Hold abiraterone, medical 
management of edema, consider 
eplerenone. 
 
Once resolved to ≤Grade 1, reinitiate 
abiraterone at full dose. 
 
If toxicity recurs, hold abiraterone 
until resolved to ≤ Grade 1, and 
reinitiate at reduced dose of 750 mg 
daily. 
 
If toxicity recurs despite first dose 
reduction, hold abiraterone until 
resolved to ≤ Grade 1, and reinitiate 
at a further reduced dose of 500 mg 
daily. 
 
If toxicity recurs despite second dose 
reduction and optimal hypertension 
management, discontinue 
abiraterone. 
LFT abnormalities 
≥ Grade 3 
 
Hold abiraterone, once resolved to ≤ 
Grade 1, reinitiate abiraterone at 
reduced dose of 750 mg daily. 
 
If toxicity recurs, hold abiraterone 
until resolved to ≤ Grade 1, and 
reinitiate at a further reduced dose 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
23
of 500 mg daily. 
 
If toxicity recurs despite second dose 
reduction and discontinuation of 
other potentially hepatotoxic 
medications, discontinue 
abiraterone. 
All other AE’s 
related to 
abiraterone ≥ 
Grade 3 
 
Hold abiraterone, once resolved to ≤ 
Grade 2, reinitiate abiraterone at 
reduced dose of 750 mg daily. 
 
If toxicity recurs, hold abiraterone 
until resolved to ≤ Grade 2, then 
reinitiate treatment at a further 
reduced dose of 500 mg daily. 
 
If toxicity recurs despite second dose 
reduction, discontinue abiraterone. 
 
Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment.  If a strong CYP3A4 
inducer must be co-administered, increase abiraterone acetate dosing frequency to twice a day only 
during the co-administration period (e.g., from 1000 mg once daily to 1000 mg twice a day).  If co-
administration of the strong inducer is discontinued, abiraterone acetate should be returned to the dose 
and frequency used prior to initiation of the strong CYP3A4 inducer. 
 
5.3.2 Radium-223 
Radium-223 dose level adjustments are not permitted.  Radium-223 dichloride, 50 kBq/kg body weight, 
will be administered as a bolus intravenous (IV) injection (up to 1 minute) at intervals of every 4 weeks 
for up to 6 cycles (55kBq/kg body weight after implementation of the NIST update). 
Every effort will be made to administer radium-223 according to schedule. 
 
Adverse Event 
Action 
Further Action and/or Maintenance 
Neutropenia ≥ 
Grade 3 
 
Hold radium-223, if resolved to ≤ 
Grade 2 within 14 days, resume 
radium-223 at its full dosing. 
 
If neutropenia persists for >14 days, 
discontinue radium-223. 
Thrombocytopenia 
≥ Grade 3 
 
Hold radium-223, if resolved to ≤ 
Grade 2 within 14 days, resume 
radium-223 at its full dosing. 
 
If thrombocytopenia persists for >14 
days, discontinue radium-223. 
Anemia ≥ Grade 3 
 
Hold radium-223, if resolved to ≤ 
Grade 2 within 14 days, resume 
radium-223 at its full dosing. 
 
pRBC transfusion permitted between 
drug administrations. 
 
If anemia persists for >14 days 
despite supportive transfusions, 
discontinue radium-223. 
All other AE’s 
related to radium-
223 ≥ Grade 3 
 
Hold radium-223, if resolved to ≤ 
Grade 2, resume radium-223 at its 
full dosing. 
 
If toxicity recurs, discontinue radium-
223. 
 
5.3.2.1 NIST Standardization Amendment 
The quantification of radium-223 radioactivity in Xofigo (radium-223 dichloride; BAY 88-8223) is based 
on the primary standardization performed by the US NIST.  National Institute of Standards and 

PRINT - last revised: 11/04/2018 
The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
24
Technology prepares the standard reference material (SRM) using an official dial setting (primary 
standardization) as published [43]. The NIST SRM is used to calibrate the instruments in production and 
quality control for both the drug substance and drug product. Additionally, the NIST SRM is used to 
prepare the NIST traceable Ra-223 reference materials which are then sent to the end-users (e.g., 
nuclear medicine laboratory physicians or technicians) for dial-setting of their dose calibrators, to allow 
verification of the patient dose. In 2014, NIST performed a re-assessment of the primary standardization 
based on preliminary information suggesting a potential discrepancy of approximately 8-10% between 
the published NIST primary standardization [43] and results obtained by other national metrology 
institutes (United Kingdom, Germany, Japan). After completion of the re-assessment, NIST reported 
their findings and had issued a revised NIST SRM in 2015 [44]. The discrepancy in the NIST 
standardization was determined to be −9.5% between activity values obtained using the old reference 
standard relative to the new primary standardization. Consequently, the current numerical values need 
to be corrected by approx. + 10.5%. The current NIST standard for radium-223 dichloride will remain in 
effect until the FDA has fully approved the regulatory variation submitted for Xofigo and is anticipated in 
the 2nd quarter of 2016.  All sites are expected to begin preparation for the updated NIST 
standardization and obtain all necessary IRB approvals. Bayer will continue to notify sites about the 
status of the regulatory approval and the date that the updated NIST standardization is to be 
implemented. Upon notification, and prior to the implementation, all sites are expected to add a new 
dial setting to their dose calibrators for the new NIST standardization for radium-223 dichloride, which 
should be documented on the appropriate study forms. The change in the numerical description of the 
patient’s dose, product strength and labeled vial activity does not impact the safety or efficacy of Xofigo. 
The change in the NIST radium-223 standard has no impact on subjects; dose subjects are receiving, and 
will continue to receive. Subjects will receive the same actual dose and volume that was studied in Study 
15245 (BC1-06 dosimetry study) and is associated with the proven safety and efficacy of radium-223 
dichloride, though the stated nominal radiation dose received is being updated to reflect the new 
standard. 
 
The change in the numerical description of the patient’s dose, product strength and labeled 
vial activity does not impact the safety or efficacy of Xofigo. The change in the NIST radium-223 standard 
has no impact on subjects; dose subjects are receiving, and will continue to receive. Subjects will receive 
the same actual dose and volume that was studied in Study 15245 (BC1-06 dosimetry study) and is 
associated with the proven safety and efficacy of radium-223 dichloride, though the stated nominal 
radiation dose received is being updated to reflect the new standard. 
 
5.3.2.2 Dose calibration 
Radium-223 dichloride can be measured in a normal dose calibrator instrument. When written 
approvals for the use of Radium-223 dichloride from the Radiation Protection Agency for the specific 
center have been received by the sponsor, a vial of Radium-223 dichloride for technical use will be sent 
to the study center. (A new reference vial will be sent to each center corresponding to the updated NIST 
reference material).  Different clinical study centers possess dose calibrators from various suppliers; 
thus, the isotope calibration factor may differ from center to center. Consequently, each center must 
perform the Radium- 223 dichloride dial setting on their relevant dose calibrator(s) (upon notification by 
Bayer each center is required to update the dial settings to correspond to the new NIST standard). The 
current dial settings are to remain in effect until Bayer obtains full approval from the FDA for 
implementation.  In preparation for implementation of the new dial setting, the clinical study center will 
receive a sealed vial labeled NIST standard containing a Radium-223 dichloride solution for calibration 
only. The vial is identical to the vials used for study treatment. The amount of Radium- 223 dichloride in 

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The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
25
the vial will be stated on the label. Instructions for the dial setting, including the calibration log form, will 
be enclosed with the dispatch of the calibration sample. 
 
All sites will be notified by Bayer when final regulatory approval from the FDA is in place and the 
updated NIST standardization is to be implemented. 
 
5.3.2.3 Dose calculation 
The dosage of Radium-223 dichloride is 50 kBq/kg body weight (55kBq/kg after NIST update). The 
patient dose is calculated based on date of injection, a decay correction (DK) factor specific to number of 
days from reference date applied to correct for physical decay of radium-223 , and patient weight. . A 
table with DK values according to physical decay of the study medication will be provided with every 
shipment of Radium-223 dichloride. Radium-223 is an alpha particle emitter with a physical t1/2 of 11.4 
days. The radioactive concentration at the reference date is 1,000 kBq/mL (1,100 kBq/mL after 
implementation of NIST update).  
 
5.3.3 Cabazitaxel and Carboplatin 
To continue treatment, patients should have an absolute neutrophil count ≥1,500 cells/mm3, platelets 
≥75,000 cells/mm3, and non-hematologic toxicities attributed to the combination of cabazitaxel and 
carboplatin resolved to ≤ Grade 2.  Specific AE’s and their management strategies are specified below. 
The two agents have some overlapping toxicities, and since they are being given in combination, should 
dose reduction become necessary, we will favor dose reducing carboplatin first over cabazitaxel, as 
cabazitaxel has demonstrated OS benefit in mCRPC patients.  Any return to protocol dose level after 
dose reduction must follow documentation of AE resolution and discussion with the Primary 
Investigator. 
 
Every effort will be made to administer the full dose regimen to maximize dose-intensity. 
If possible, toxicities should be managed symptomatically. If toxicity occurs, the appropriate treatment 
will be used to improve signs and symptoms including antiemetics for nausea and vomiting, 
antidiarrheals for diarrhea, and antipyretics, and/or antihistamines for drug fever. 
 
Dose can be reduced for cabazitaxel when necessary as described in following sections. The dose, which 
has been reduced for toxicity, must not be re-escalated.  Only one dose reductions will be allowed per 
patient. If a second dose reduction is required per the modifications below, the patient should 
discontinue study treatment.  Treatment may be delayed no more than 2 weeks to allow recovery from 
acute toxicity. In case of treatment delay greater than 2 weeks, patient should discontinue cabazitaxel. 
 
Blood counts will be performed in case of fever or infection.  No dose modification will be made for 
anemia; patients will be supported appropriately by the treating physician (the investigator can refer to 
ASCO guidelines).  Study treatment should not be given to patients with neutrophil counts <1,500 
cells/mm3.  Deaths due to sepsis following severe neutropenia have been reported in patients treated 
with cabazitaxel.  Neutropenic complications should be managed promptly with antibiotic support.  
Infections concomitant with grade 3-4 neutropenia should be reported with the term “neutropenic 
infection” in the eCRF. 
 
No dose modification will be made for anemia; patients will be supported appropriately by the treating 
physician (the investigator can refer to ASCO guidelines). 
 
Adverse Event 
Action 
Further Action and/or Maintenance 

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(NIST) standardization update (agreed on 17 MAR 2015). 
26
Neutropenia 
Grade 2 
 
Hold cabazitaxel and carboplatin until 
ANC ≥ 1,500 cells/mm3, then 
reinitiate treatment with cabazitaxel 
at full dose and carboplatin reduced 
by 20% based on AUC. 
 
If toxicity recurs, hold until ANC ≥ 
1,500 cells/mm3, then reinitiate 
treatment with the same carboplatin 
dose reduction, and cabazitaxel at 
reduced dose of 15 mg/m2. 
 
If toxicity recurs despite cabazitaxel 
and carboplatin dose reductions and 
pegfilgrastim prophylaxis, 
discontinue treatment. 
Neutropenia ≥ 
Grade 3 
 
Hold cabazitaxel and carboplatin until 
ANC ≥ 1,500 cells/mm3, then 
reinitiate treatment with cabazitaxel 
at 15 mg/m2 and carboplatin reduced 
by 20% based on AUC. 
 
If toxicity recurs despite cabazitaxel 
and carboplatin dose reductions and 
pegfilgrastim prophylaxis, 
discontinue treatment.  
Febrile 
Neutropenia or 
Neutropenic 
Infection ≥ Grade 
3 
 
Hold cabazitaxel and carboplatin until 
ANC ≥ 1,500 cells/mm3, then 
reinitiate treatment with cabazitaxel 
at 15 mg/m2 and carboplatin reduced 
by 20% based on AUC. 
 
If toxicity recurs despite cabazitaxel 
and carboplatin dose reductions and 
pegfilgrastim prophylaxis, 
discontinue treatment. 
Anemia 
 
No dose modification will be made 
for anemia 
 
Patients will be supported 
appropriately by the treating 
physician (the investigator can refer 
to ASCO guidelines). 
 
Thrombocytopenia 
Grade 2 
 
Hold cabazitaxel and carboplatin until 
recovery to grade ≤ 1 (platelets ≥ 
75,000 cells/mm3), then reinitiate 
treatment with cabazitaxel at full 
dose and carboplatin reduced by 20% 
based on AUC. 
 
Thrombocytopenia 
Grade 3 
 
Hold cabazitaxel and carboplatin until 
platelets ≥ 75,000 cells/mm3: 
o If no delay, then reinitiate 
treatment with cabazitaxel at 
full dose and carboplatin 
reduced by 20% based on 
AUC. 
o If delay, then reinitiate 
treatment with cabazitaxel at 
15 mg/m2 and carboplatin 
reduced by 20% based on 
AUC. 
 
If toxicity recurs without cabazitaxel 
dose reduction, then reinitiate 
treatment with the same carboplatin 
dose reduction, and cabazitaxel at 
reduced dose of 15 mg/m2. 
 
If toxicity recurs despite cabazitaxel 
and carboplatin dose reductions, 
discontinue treatment. 
Thrombocytopenia 
Grade 4 
 
Hold cabazitaxel and carboplatin until 
platelets ≥ 75,000 cells/mm3, then 
reinitiate treatment with cabazitaxel 
at 15 mg/m2 and carboplatin 
 
If toxicity recurs despite cabazitaxel 
and carboplatin dose reductions, 
discontinue treatment. 

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(NIST) standardization update (agreed on 17 MAR 2015). 
27
reduced by 20% based on AUC. 
Diarrhea ≥ Grade 3  
Hold cabazitaxel and carboplatin until 
resolved to ≤ Grade 2, then reinitiate 
treatment with cabazitaxel at 
reduced dose of 15 mg/m2 and 
carboplatin reduced by 20% based on 
AUC 
 
If toxicity recurs despite cabazitaxel 
and carboplatin dose reduction and 
symptomatic support, discontinue 
treatment. 
Hepatic 
Impairment 
 
Mild impairment (total bilirubin >1 to 
≤1.5 x ULN or AST >1.5 x ULN), keep 
cabazitaxel at 20 mg/m2. 
 
Moderate impairment (total bilirubin 
>1.5 to ≤3.0 x ULN and AST = any), 
reduce cabazitaxel to 15 mg/m2 
 
Severe impairment (total bilirubin 
>3.0 x ULN), cabazitaxel is 
contraindicated in patients with 
severe hepatic impairment. 
 
Other AE’s* 
related to 
cabazitaxel and 
carboplatin ≥ 
Grade 3  
 
Hold cabazitaxel and carboplatin until 
resolved to ≤ Grade 1, then reinitiate 
treatment with dose reduction left to 
the investigator’s judgment. 
 
If requires >1 dose reduction of 
cabazitaxel or >1 dose reduction of 
carboplatin, discontinue treatment. 
*except fatigue, local reaction, fluid retention, anemia and other toxicities that merely are 
uncomfortable but do not cause serious morbidity to patients. 
 
5.3.3.1 Specific to Cabazitaxel 
 
Concomitant Medications 
Avoid concomitant strong CYP3A4 inhibitors during cabazitaxel treatment.  If a strong CYP3A4 inhibitor 
must be co-administered, decrease cabazitaxel dose by 25%.  If co-administration of the strong CYP3A4 
inhibitor is discontinued, cabazitaxel should be returned to the dose used prior to initiation of the strong 
CYP3A4 inhibitor. 
Allergy (Anaphylactic and Hypersensitivity reactions) 
Hypersensitivity reactions that occur despite premedication are very likely to occur within a few minutes 
of start of the first or of the second infusion of cabazitaxel. Therefore, during the 1st and the 2nd 
infusions, careful evaluation of general sense of well being and of blood pressure and heart rate will be 
performed for at least the first 10 minutes, so that immediate intervention would occur in response to 
symptoms of an untoward reaction. 
 
Facilities and equipment for resuscitation along with the medications (i.e., antihistamine, 
corticosteroids, aminophylline, and epinephrine) must be immediately available. If a reaction occurs, the 
specific treatment that can be medically indicated for a given symptom (e.g., epinephrine in case of 
anaphylactic shock, aminophylline in case of bronchospasm, etc) will be instituted. In addition, it is 
recommended to take the measures listed below: 
 
Mild: localized cutaneous reaction, such as: 
 
Consider decreasing the rate of infusion until 

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The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
(NIST) standardization update (agreed on 17 MAR 2015). 
28
pruritus, flushing, rash. 
recovery of symptoms, stay at bedside 
 
Complete cabazitaxel infusion at the initial 
planned rate. 
Moderate: Generalized pruritus, more severe 
flushing or rash, mild dyspnea, hypotension with 
systolic B.P. >80 mmHg 
 
Stop cabazitaxel infusion 
 
Give IV diphenhydramine 50 mg and/or IV 
dexamethasone 10 mg 
 
Once all signs and/or symptoms of 
hypersensitivity reaction disappear, 
cabazitaxel may be reinfused within 24 hours 
from the interruption, if medically appropriate, 
and whenever possible. 
 
Re-administer premedication regimen when 
cabazitaxel is reinfused more than 3 hours 
after the interruptionAdminister cabazitaxel 
over 2 hours for all subsequent infusions 
Severe: bronchospasm, generalized urticaria, 
hypotension with systolic B.P. ≤80 mmHg, 
angioedema. 
 
Stop cabazitaxel infusion 
 
Give IV diphenhydramine 50 mg and/or IV 
dexamethasone 10 mg 
 
Add epinephrine or bronchodilators and/or IV 
plasma expanders if indicated 
 
Once all signs and/or symptoms of 
hypersensitivity reaction disappear, 
cabazitaxel may be reinfused within 24 hours 
from the interruption, if medically appropriate, 
and whenever possible 
 
Re-administer premedication regimen when 
cabazitaxel is reinfused more than 3 hours 
after the interruption 
 
Administer cabazitaxel over 2 hours for all 
subsequent infusions 
 
If a severe reaction recurs, patient will go off 
protocol therapy 
Anaphylaxis (Grade 4 reaction) 
 
Withdraw treatment 
 
Nausea/Vomiting 
A prophylactic anti-emetic treatment should be given to the patients in all cycles. The use of 
metoclopramide is recommended. More aggressive anti-emetic prophylaxis (i.e., ondansetron, etc.) 
should be given to the patient who has experienced grade ≥3 nausea/vomiting in a preceding cycle. If 
despite the appropriate medication, grade ≥3 nausea/vomiting still occur, reduce the dose of 
cabazitaxel. If despite dose reduction and prophylaxis, nausea/vomiting still occur at grade ≥3, the 
patient should be withdrawn from treatment with cabazitaxel. 
 
Stomatitis 
If grade 3 stomatitis occurs, cabazitaxel should be withheld until resolution to grade ≤1. Treatment may 
then be resumed, but the dose of cabazitaxel should be reduced for all subsequent doses. In case of 
grade 4 stomatitis, the patient will be withdrawn from treatment with cabazitaxel. 
 

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(NIST) standardization update (agreed on 17 MAR 2015). 
29
Hematuria 
An imbalance in the incidence of hematuria was observed in the Phase III study in second line mCRPC 
(EFC6193).  More hematuria was reported in cabazitaxel arm versus mitoxantrone arm (62 
patients/16.7% versus 14 patients/3.8%).  In cabazitaxel arm, no clear possible explanation such as local 
infection/obstruction/progression, or anticoagulation/aspirin therapy, or thrombocytopenia was found 
for 21 patients. In addition, in prior studies conducted in metastatic breast cancer, a total of 6 patients 
(2 in the ARD6191 and 4 in the TCD6945) experienced cystitis without local infection including 5 
hemorrhagic cystitis (3 cystitis were documented with biopsy).  Therefore, in case of hematuria with no 
clear possible explanation every effort should be undertaken to document the cause (e.g., urine 
cultures, urinary tract ultrasound, and if no cause identified cystoscopy with or without biopsy). 
 
Neurological toxicity 
Dose modification should be performed as follows: 
 
Grade ≤1: No change 
 
Grade 2: Retreat with reduced dose 
 
Grade 3: Patient will be withdrawn from treatment with cabazitaxel 
 
Other Toxic Effects 
Any measures such as frozen gloves or socks or scalp cooling cap to prevent nail toxicity or alopecia are 
left to the investigator’s judgment. 
 
 
5.3.4 Enzalutamide 
For any grade 3 or higher adverse event related to enzalutamide, enzalutamide should be withheld until 
symptoms improve to Grade 2 or lower toxicity.  A maximum of 2 dosage reductions will be allowed. 
 
Adverse Event 
Action 
Further Action and/or Maintenance 
Any AE related to 
enzalutamide ≥ 
Grade 3  
 
Hold enzalutamide until symptoms 
improve to ≤ Grade 2, then reinitiate 
at reduced dose of 120 mg daily. 
 
If toxicity recurs, hold until symptoms 
improve to ≤ Grade 2, then reinitiate 
at 80 mg daily. 
 
If toxicity recurs again, then 
discontinue enzalutamide. 
 
Concomitant use of strong CYP2C8 inhibitors should be avoided if possible.  If patients must be co-
administered a strong CYP2C8 inhibitor, reduce enzalutamide to 80 mg once daily.  If co-administration 
of the strong inhibitor is discontinued, enzalutamide should be returned to the dose used prior to 
initiation of the strong CYP2C8 inhibitor. 
Concomitant use of strong CYP3A4 inducers should be avoided if possible.  If patients must be co-
administered a strong CYP3A4 inducer, increase enzalutamide from 160 mg to 240 mg once daily.  If co-
administration of the strong CYP3A4 inducer is discontinued, enzalutamide should be returned to the 
dose used prior to initiation of the strong CYP3A4 inducer. 
5.3.5 Prednisone 
For any grade 3 or higher adverse event related to prednisone, prednisone should be withheld until 
symptoms improve to Grade 2 or lower toxicity.  A maximum of 1 dosage reduction will be allowed. 
 

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(NIST) standardization update (agreed on 17 MAR 2015). 
30
 
 
 
Adverse Event 
Action 
Further Action and/or Maintenance 
Any AE related to 
prednisone ≥ 
Grade 3  
 
Hold prednisone until symptoms 
improve to ≤ Grade 2, then reinitiate 
at reduced dose of 5 mg daily. 
 
If toxicity recurs, then discontinue 
prednisone. 
 
5.4 Pharmacovigilance Specifications 
 
5.4.1 Sanofi - Obligations and Responsibilities of the IST/ISS Sponsor 
The IST/ISS sponsor warrants that the study will be performed in compliance with all applicable local and 
international laws and regulations, including without limitation ICH E6 guidelines for Good Clinical 
Practices.  
 
The IST/ISS sponsor shall be responsible for the respect of all obligations required by applicable 
local and international laws and regulations.  
 
The sponsor shall be responsible for ensuring submission of required expedited and periodic 
reports to the appropriate Health Authority (HA), the Ethics Committee and investigators of 
each country participating in the IST/ISS (based on applicable regulations). 
 
The IST/ISS sponsor is responsible for providing any “Dear Investigator Letter” (DIL) for new 
safety finding received from Sanofi group entity to the investigators and Ethics Committee in 
each country participating in the study. 
 
Investigators are required to assess if there is a reasonable causal relationship with the study 
drug/treatment regimen administered for each reported AE.  “Reasonable causal relationship” 
means that, in the Investigators best clinical judgment, there are facts/evidence or arguments to 
suggest a causal relationship. Possible answers are ‘Yes’ or ‘No'. 
 
The sponsor must report the following information in English to the Sanofi group entity 
Pharmacovigilance contact: 
1. Routine transmission of: 
a. All Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI), if 
any. These events must be transmitted within 24 hours of awareness of the 
Investigator’s awareness or identification of the event.  
b. Results of any relevant complementary exams performed to obtain the final 
diagnosis of any SAE (e.g., hospital discharge summary, autopsy, consultation) will 
be made available to Sanofi group entity upon request. 
2. Other events or periodic reports (e.g. Development Safety Update Report (DSUR)), 
submitted to Regulatory Authority must be transmitted at the time of submission. 
3. Other significant safety issues or findings in a study pertaining to safety of product must be 
transmitted within 24 hours of awareness. (e.g., Data Safety Monitoring Board 
recommendations) 
4. The study report of any IST/ISS must contain a section describing safety review and 
conclusion. 
5. The reference safety information to be used by the IST/ISS sponsor for evaluation of 
expectedness of adverse events of cabazitaxel shall be the Investigator’s Brochure. 
5.4.2 
Sanofi Group Entity Pharmacovigilance Contact  
IST/ISS Investigators will notify Sanofi via fax or email, attention Sanofi Pharmacovigilance (PV) 
 

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(NIST) standardization update (agreed on 17 MAR 2015). 
31
Fax/email of SAE Reports to Sanofi: 
Fax: 908-203-7783   
E-mail:  CL-CPV-Receipt@sanofi.com 
 
5.4.3 Bayer - Obligations and Responsibilities of the IST/ISS Sponsor 
All serious adverse events should be reported to Bayer within 24 hours.  In the event of such an event, 
the investigator should refer to the Pharmacovigilance section of the contract for reporting procedures 
and report SAE to Bayer. 
 
Requirements for Reporting of Serious Adverse Events:  
All SAEs must be reported to Bayer within 24 hours of the Principal Investigator’s awareness and must 
include the following minimum information:  
1. The name and contact information of the reporter  
2. The name of the study drug(s)  
3. A description of the reported SAE  
4. A patient identified by one or more of the following:  
a. Patient initials  
b. Patient number  
c. Knowledge that a patient who experienced the adverse event exists  
d. Age  
e. Sex  
 
An investigator assessment of study drug causality. For studies with combination therapy, a separate 
causality assessment should be provided for each study drug.  
Additional data which would aid the review and causality assessment of the case include but are not 
limited to:  
The date of onset  
The severity  
The time from administration of study drug(s) to start of the event  
The duration and outcome of the event  
Any possible etiology for the event  
The final diagnosis or syndrome, if known  
Action(s) taken, if any 
 
5.4.4 Bayer Global Pharmacovigilance Contact 
The Investigator may report serious adverse drug reactions (SADRs) using either: 
1. An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html   
2.  A MedWatch form available at: http://www.fda.gov/medwatch/  
 
All reports shall be sent electronically to:  
 
Electronic Mailbox:  
 
DrugSafety.GPV.US@bayer.com  

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(NIST) standardization update (agreed on 17 MAR 2015). 
32
Facsimile:   
 
 
(973) 709-2185  
 
Address: 
 
 
Global Pharmacovigilance - USA  
Mail only: 
 
 
Bayer HealthCare  
 
 
 
 
P.O. Box 915 
 
 
 
 
Whippany, NJ 07981-0915 
 
Address:   
 
 
100 Bayer Blvd., Whippany, NJ 07981  
FDX or UPS only   
 
67 Whippany Road, Whippany, NJ 07981 for UPS  
 
Reports for all Bayer products can also be phoned in via the Clinical Communications Dept 
Phone:   
 
 
1-888-842-2937 
 
6. Follow Up, Laboratory Testing, and Diagnostic Imaging 
Clinic visits will be scheduled at the beginning of each treatment module, with blood samples taken for 
serum testing of CBC, comprehensive metabolic panel, LDH, PSA, and testosterone panel during these 
visits.  During the first (abiraterone) treatment module, laboratory tests will be repeated every 2 weeks 
for the first 4 weeks, then every 4 weeks afterwards.  Follow up and treatment visits will be scheduled 
every 4 weeks.  During second (cabazitaxel and carboplatin) treatment module, follow up, laboratory 
tests, and treatment visits will be scheduled every 3 weeks.  During the third (enzalutamide and radium-
223) treatment module, laboratory tests will be repeated every 2 weeks for the first 4 weeks, then every 
4 weeks afterwards.  Follow up and treatment visits will be scheduled every 4 weeks. 
 
Baseline evaluation, including informed consent, medical history, physical examination, vital signs, 
height, weight, performance status, laboratory testing, and imaging with CT chest/abdomen/pelvis scan 
and bone scan should be obtained no greater than 8 weeks before initiation of trial treatment regimen.   
 
Repeat CT chest/abdomen/pelvis scan and bone scan should be repeated every 12 weeks to coincide 
with the completion of each treatment module. 
 
Evaluation for adverse events will take place on all scheduled study visits during all three modules of 
treatment, as well as every 4 weeks until week 12 of the the post-treatment surveillance period.  
Monitoring for adverse events will stop after that, as patients will have been off of the rapidly cycling 
study regimen for 12 weeks, and side effects from treatment drugs would have anticipated to have 
resolved by this time. 
 
Peripheral blood will be collected in PAXgene Blood RNA tubes on the first day of each new treatment 
module, the first day of the post-treatment surveillance period, and at week 12 of the post-treatment 
surveillance period (unless there has been progression). 
 
If the external laboratory that performs the peripheral blood CTC testing is ready to receive and process 
the specimen, peripheral blood will be collected in Streck Cell-Free DNA blood collection tubes on the 
first day of each new treatment module, and the first day of the post-treatment surveillance period.  If 
not, this tube will not be drawn, as these samples cannot be frozen and stored for later analysis. 
 
During the post-treatment surveillance period, as long as disease progression has not yet been 
demonstrated, patients will adhere to every 4 week follow up and lab draws until week 12 of the 

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(NIST) standardization update (agreed on 17 MAR 2015). 
33
surveillance period.  After week 12, lab draws will remain every 4 weeks, but interval for office visits will 
be extended to every 12 weeks.  Imaging will be performed every 12 weeks until disease progression. 
 
Once disease progression is demonstrated during the post-treatment surveillance period, the patient 
will come off study, and the schedule for follow up, labs, imaging, AE monitoring, and treatment will no 
longer be defined by the timepoints designated by the trial.  Long term survival data will be collected via 
chart review and phone discussions.    
 
Once off study, patients will remain eligible for any of the treatment agents that were already received 
as part of the study, although how the patient responded and tolerated the drug previously will be taken 
into consideration.  The selection of agent (or combination of agents), as well as the interval for follow 
up, labs, and imaging, will be at the treating physician’s discretion. 
 
 
 
Baseline 
Treatment 
 
 
Post-
Treatment 
Surveillance* 
Module 1 
Module 2 
Module 3 
Informed Consent 
Once 
 
 
 
 
Medical History 
Once 
 
 
 
 
Physical Examination 
Once 
Q4 weeks 
Q3 weeks 
Q4 weeks 
Q4 weeks until 
week 12, then 
q12 weeks** 
Vital Signs/Weight 
Once 
Q4 weeks 
Q3 weeks 
Q4 weeks 
Q4 weeks until 
week 12, then 
q12 weeks** 
Performance Status 
Once 
Q4 weeks 
Q3 weeks 
Q4 weeks 
Q4 weeks until 
week 12, then 
q12 weeks** 
CBC with differential 
Once 
Q4 weeks 
Q3 weeks 
Q4 weeks 
Q4 weeks** 
CMP 
Once 
Q2 weeks for 
the first 4 
weeks, then 
Q4 weeks 
Q3 weeks 
Q2 weeks for 
the first 4 
weeks, then 
Q4 weeks 
Q4 weeks** 
PSA 
Once 
Q4 weeks 
Q3 weeks 
Q4 weeks 
Q4 weeks** 
Testosterone 
Once 
Q4 weeks 
Q3 weeks 
Q4 weeks 
Q4 weeks** 
LDH 
Once 
Q4 weeks 
Q3 weeks 
Q4 weeks 
Q4 weeks** 
ECG 
Once 
Q4 weeks 
 
 
 
AE Monitoring 
Once 
Q4 weeks 
Q3 weeks 
Q4 weeks 
Q4 weeks until 
week 12 
CT C/A/P 
Once 
Q12 weeks 
Q12 weeks 
Q12 weeks 
Q12 weeks** 
Bone Scan 
Once 
Q12 weeks 
Q12 weeks 
Q12 weeks 
Q12 weeks** 
PAXgene Blood RNA 
tube 
None 
At start of 
module 
At start of 
module 
At start of 
module 
At start of 
surveillance, 
then Q12 
weeks, 
until week 12 
Streck Cell-Free DNA 
None 
At start of 
At start of 
At start of 
At start of 

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(NIST) standardization update (agreed on 17 MAR 2015). 
34
blood collection 
tube*** 
module*** 
module*** 
module*** 
surveillance*** 
*Once disease progression has been demonstrated, the schedule for follow up, blood work, imaging, 
and AE monitoring is no longer defined by the timepoints designated by the trial.  Instead, intervals will 
be at the discretion of the treating physician, depending on decisions made on subsequent lines of 
therapy. 
** Until disease progression 
***Only if the external laboratory that performs the peripheral blood CTC analysis is ready to receive 
and process the specimen 
 
6.1 Criteria for Discontinuation of Study Regimen 
The study regimen may be discontinued for any of the following reasons: 
 
Intolerable, recurrent, or sustained adverse effects of the study regimen despite appropriate dose 
reduction and best supportive management. 
 
Noncompliance with study regimen or follow up appointments. 
 
Patient choice to withdraw from trial. 
 
Investigator or physician discretion. 
 
As defined by PCWG2 guidelines, the earliest time point that PSA progression can be determined is at 12 
weeks.  This is in line with the understanding that a favorable PSA response may be delayed for 12 
weeks or more, even with cytotoxic chemotherapy.  Similarly, the earliest time point for determination 
of radiographic progression is also at the end of each module (12 weeks) given trial design. 
 
The design of the treatment schedule is such that the treatment modality will be changed regardless of 
response observed.  For patients whose disease are found to be progressing at the end of a treatment 
module (12 weeks), their treatment is already planned to be transitioned to another agent, which is in 
line with standard of care for disease progression, and would not constitute a need to discontinue the 
study regimen and withdraw from trial. 
 
Patients who do not complete all three treatment modules will be considered dropped out, and not 
included in the primary and secondary endpoint analyses.  However, whenever possible, attempts will 
be made to collect overall survival data of patients that have discontinued the study regimen. 
 
7. Statistical Plan 
In this trial, all patients will be treated using the rapid-cycling non-cross reactive treatment model as 
detailed above.  Given that cycling therapies is a novel concept in prostate cancer management, there 
are no similar trials or statistics available that can be used for direct historical comparison.  The 3 month 
time to disease progression quoted as part of the statistical design of this clinical trial is obtained 
primarily from the AFFIRM and PREVAIL trials, where mCRPC patients were randomized to receive either 
enzalutamide or placebo. 
 
The placebo arm of the AFFIRM study is most closely comparable to our patient cohort, in that they will 
have received multiple different prostate cancer therapies, and will be actively surveyed on primary ADT 
alone following completion of the rapidly cycling regimen.  The AFFIRM placebo arm had a median time 
to PSA progression of 3.0 months, and radiographic PFS of 2.9 months [4].  However, though our 
patients will be treatment-experienced following the 9 months of treatment, they will not be considered 
treatment-refractory as were those enrolled on AFFIRM.  We gain additional insight from the PREVAIL 
trial into the natural history and rate of progression of CRPC that has not yet developed multi-drug 

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35
resistance.  In the cohort of treatment-naïve mCRPC men receiving placebo, median time to PSA 
progression was 2.8 months, and radiographic PFS 3.9 months [7]. 
 
As our composite primary endpoint utilizes the earliest evidence of PSA or radiographic progression to 
define disease progression, we believe that 3 months is a reasonable control. 
 
Another trial considered as a historical control is the ASCENT trial, which treated chemotherapy-naïve 
mCRPC patients with intermittent docetaxel [45].  Of the patients that met study criteria to receive a 
break from chemotherapy, the median duration of the first chemotherapy holiday was 18 weeks (4.5 
months).  This figure is higher than 3 months, but did not factor in patients who did not meet 
requirements to go on drug holiday.  This cohort also had no prior exposure or resistance to abiraterone 
or enzalutamide, which likely factors into the longer interval to progression.  This study still serves as a 
good internal check, to demonstrate that our 3-month time to disease progression is reasonably chosen. 
 
The median time to PSA progression in our cohort of patients will be estimated using a Cumulative 
Incidence Competing Risk (CICR) analysis with mortality from any cause considered a competing risk.  To 
test whether the estimated median time to progression is significantly greater than historical time to 
progression of 3 months, a likelihood ratio test will be used.  The maximum likelihood estimates of 
parameters, using either the exponential or Weibull distribution, obtained from the observed data will 
be compared to  a median time to disease progression of 3 months [46].  For a study with 36 months 
accrual and a follow-up period of 24 months from the last patient’s entry, a sample size of 33 patients 
that complete all three treatment modules of the study regimen will provide 90% power for a one-sided 
test at the 5% level to detect an increase in median time to disease progression from 3 months to 5 
months [47].  We will plan to screen 60 patients (treat a total of 40 patients) on study in order to 
account for any potential patient dropout, defined as anyone who does not complete all three 
treatment modules. 
 
In addition to the above, we will also perform an intention-to-treat analysis of all enrolled patients in 
order to account for any early progressions or deaths. 
  
Overall survival will be estimated using the method of Kaplan-Meier.  Comparison will be made with 
historical OS data from the PREVAIL and COU-AA-302 trials (32.4 and 34.7 months, respectively) [3, 7] 
where treatment-naïve mCRPC patients received long term follow up during which they received 
multiple different active therapies. 
 
PSA response rates to the overall regimen and each individual treatment module will be evaluated 
independently and compared to historical controls and presented as descriptive statistics.  From large 
phase III pre-chemotherapy studies, abiraterone and enzalutamide have PSA response rates of 62% [3] 
and 78% [7], respectively.  Past experience with regimens that include a taxane and a platinum agent, 
PSA response rates have ranged 69-88% [32, 33].  There is limited data available for cabazitaxel and 
carboplatin, but recently reported phase II trial of this combination demonstrated a 52% partial 
response rate as evaluated by RECIST radiographic criteria [35].   
 
Since baseline PSA levels for treatment modules 2 and 3 will be affected by the agents introduced in 
prior treatment modules, we expect PSA response rates of the individual modules to be lower than 
expected from historical comparison.  However, if a patient is considered to be a responder based on 
PSA in a previous treatment module, and the PSA remains stable or continues to decline on a 

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36
subsequent treatment module, argument can be made that the patient is a responder to that module as 
well even if PSA declines of 50% are not attained. 
 
Changes to alkaline phosphatase levels will be tracked for each treatment module, the overall treatment 
regimen, and at time of disease progression.  While alkaline phosphatase (ALP) is not a well-studied 
endpoint in prostate cancer trials, its serum levels often correlate with bone metastases status [48], and 
normalization of ALP levels has been suggested to predict better survival [49].  ALP levels will be 
compared to the upper limits of normal (ULN) for all laboratory testing performed in the study period 
and calculated as a ratio. ALP will be considered to be persistently abnormal if the levels are 
continuously greater than a ratio of 1 and considered to normalize if there is at least one value with a 
ratio of 1 or less. Fine and Gray’s Competing Risk Regression (CRR) will be used to estimate a hazard 
ratio comparing the risk of progression betweein patient groups with abnormal and normalized ALP 
levels while accounting for the presence of competing risks. This analysis will be performed to 
determine whether normalized ALP levels, correlates with time to disease progression.   
 
Safety will be assessed through summaries of adverse events, vital signs, physical examinations, ECGs, 
and clinical laboratory test data.  The number and percentage of patients with adverse events will be 
presented as descriptive statistics. 
The six-gene scores following each individual treatment module will be compared to baseline pre-
treatment scores using a paired T-test.  Changes to the six gene score over sequential time points will 
also be evaluated using linear mixed model.  Additionally, we will perform statistical analysis to 
determine whether the baseline six-gene scores can predict treatment response or whether the post-
treatment six-gene score is associated with clinical treatment outcomes, including PSA and radiographic 
response. 
The number and percentage of men with AR-V7 positivity will be evaluated at baseline, with the 
completion of each treatment module, and at follow up.  The prevalence of AR-V7 in treatment-naïve 
mCRPC patients remain the subject of further investigation, but we can assume it to be approximately 
one third [39].  We will track AR-V7 expression changes over the course of treatment.  We hypothesize 
that men who are either AR-V7 positive at baseline or develop it over the course of treatment, will have 
similar outcomes to AR-V7 negative men with the rapidly-cycling treatment regimen.  Fine and Gray’s 
Competing Risk Regression will be used to estimate a hazard ratio comparing time to disease 
progression between the two groups. 
8. Data Handling and Record Keeping 
8.1 Electronic Data Capture (EDC) System 
 
All eCRFs will be entered directly into a web-based electronic research application portal known as 
REDCap. REDCap’s role-based access control security and audit capability ensures that the research data 
is protected from unauthorized access, modification, and exposure. Key features of this web-based 
database system include allowing access and data entry from multiple sites, with each site having a 
separate pool of data as necessary. All data stored in the REDCap system is backed up daily. Detailed 
audit services include any data field level changes, who made the changes, when the changes were 
made, the old value and the new value. Data from REDCap can easily be extracted to excel or flat text 
file formats for easy import into SAS or other statistical software packages. 
 

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37
 
 
 
8.2 Verification of EDC System 
 
Once the database has been set up the PI will test the system. The testing will include confirmation of 
the proper functioning of valid value checks, subject ID generation, derived variable computations, data 
extracts and system reports.  
 
8.3 Entering data 
 
Since electronic CRFs will be used, data entry will be conducted onsite by clinicians who have been 
granted appropriate access to do so. 
 
 
8.4 Data Validation Process 
 
As part of the data validation process, edit check programs will be embedded in the database thru valid-
value, valid-range and missing value alerts specified for each field as necessary. Valid-value edit checks 
include: 
 
 
Requiring the user to enter a coded value taken from a list that is presented on the CRF. 
If a value not on the list is entered the user will be prompted to check the value and 
enter a value on the list. 
 
Requiring the user to enter a value within a particular range of possible values for a 
continuous measure. If a value outside the range is entered the user will be prompted to 
check the value and re-enter. 
 
In addition to the univariate field alerts specified above, there will be multivariate alerts built into the 
database design: 
 
Confirming that only valid options are selected in a ‘choose all that apply’ multiple 
choice field, where the range of options deemed valid depends on some other 
parameter. 
 
Confirming that diastolic blood pressure reading is less than the associated systolic 
blood pressure reading. 
 
Confirming that “other, specify” is completed when “other” is selected. 
 
Confirming that eligibility criteria are met. 
 
As well as cross-module alerts such as: 
 
Comparing the dates and times of all assessment time points to confirm that they 
occur in an appropriate sequence. 
  
8.5 Data Cleaning and Discrepancy Management 
 
Any discrepancies identified through this process will be highlighted and corrected in the system.    
 
8.6 Data Security 

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38
 
The EDC database is approved by Mount Sinai IT Security and HIPAA and operates using high-end servers 
located in the Secured Mount Sinai Data Center. All data stored in the REDCap system is backed up daily. 
Access to the database is controlled by policies requiring the PI to authorize user and user roles. Quick 
view audit service allows authorized user to see who accessed records for view or edit and detailed 
audit services include seeing any data field level changes, who made the changes, when the changes 
were made, as well as the value before and after the change. 
 
8.7 Quality Control Procedures 
 
Comprehensive edit checks will be used to clean data. Patient data will be entered continuously. All 
changes to the data and the database structure will be recorded in an automatic audit trail. Random 
checks will be done by the PI to ensure data accuracy and completeness. A final database will be 
declared when all data has been entered, the data entry verified, the data validated and the database 
defined as clean. After declaration of a final database the data will be exported from REDCap to excel for 
import to SAS and both the database and the SAS datasets will be locked and protected from changes. 
All statistical analyses for the final analysis will be performed on the locked SAS datasets.  
 
8.8 Medical and Adverse Event Coding 
 
Coding of Adverse Events occurring during the study will be performed by the Clinical Research Manager 
according to the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 while 
coding of concomitant medications, prior anti-cancer therapy and further therapy will be performed 
according to the World Health Organization-Drug Dictionary Enhanced (WHO-DDE). These dictionaries 
contain the respective classifications of adverse events and drugs in proper classes. When dictionary 
entries and verbatim terms (either for adverse events for medications) do not directly match, the PI will 
review the entry as well as other related information such as comment fields to identify the most 
appropriate match. In the event there are compound verbatim events (either AEs or medications) listed 
in the CRF, such events must be split into more than one record for purposes of medical coding. The PI 
will be responsible for splitting the compound events into separate entries. 
 
8.9 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements 
of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 

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39
 
8.10 Records Retention 
The Investigator must retain drug disposition records (if applicable), source documents, and case 
histories designed to record all observations and other data pertinent to the investigation (e.g. case 
report form) for the maximum period required by applicable regulations and guidelines, or Institution 
procedures. 
If a change in the PI occurs, the records shall be transferred to a mutually agreed upon designee (e.g., 
another Investigator, IRB). 
 
8.11 Subject Privacy 
Patients will be informed of the extent to which their confidential health information generated from 
this study may be used for research purposes. Following this discussion, they will be asked to sign the 
HIPAA form and informed consent documents. The original signed document will become part of the 
patient’s medical records, and each patient will receive a copy of the signed document. The use and 
disclosure of protected health information will be limited to the individuals described in the informed 
consent document. 
 
It is the responsibility of the research staff to ensure that protocol subjects received, understands, and 
signs the informed consent document before enrolling the patient onto this trial. Personnel must 
provide a HIPAA form and obtain acknowledgment before the subject participates in this study. 
All subject data will be identified by a subject identification number and subject initials only, to protect 
the subject’s privacy. The data will be blinded accordingly in all data analysis. However, in compliance 
with federal guidelines, the investigator will permit a representative from Mount Sinai Health System 
audit committee to review that portion of the subject’s medical record that is directly related to the 
study. This will include all relevant study documentation including medical histories to verify eligibility, 
laboratory test results to verify transcription accuracy, X-ray reports, admission/discharge summaries for 
hospital/outpatient admissions while the subject is on-study and autopsy reports for deaths occurring 
during the study. As part of the required content of informed consent, the subject will be informed that 
his medical record may be reviewed. Should access to the medical record require a separate waiver or 
authorization, it is the PI’s responsibility to obtain such permission from the patient in writing before the 
subject is entered into the study. 
 
9. Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for 
formal approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study 
will be made in writing to the investigator and a copy of this decision will be provided to the sponsor 
before commencement of this study.  The investigator should provide a list of EC/IRB members and their 
affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  See 
Attachment D for a copy of the Subject Informed Consent Form.  This consent form will be submitted 
with the protocol for review and approval by the EC/IRB for the study.  The formal consent of a subject, 

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(NIST) standardization update (agreed on 17 MAR 2015). 
40
using the EC/IRB-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent.  
 
10. Financial Considerations 
See attached clinical trial and correlative study budget spreadsheets. 
 
11. Publication Plan 
Our abstract with preliminary results will be submitted to the American Society of Clinical Oncology 
(ASCO) Annual Meeting and the ASCO Genitourinary Cancers Symposium in early 2019. The final 
manuscript will be completed by early 2020, and be targeted for the Journal of Clinical Oncology or 
Clinical Cancer Research though the ultimate impact of the publication and target journal will depend on 
the results. 
 
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