Conditions: Prostate Cancer
Keywords: Castration resistant Prostate cancer Metastatic First-line Treatment naive Rapidly cycling Non-cross resistant
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the clinical benefits of using a rapidly cycling, non-cross reactive regimen of FDA-approved prostate cancer therapeutic agents in the management of castration resistant prostate cancer. The hypothesis is that the identification of optimal combinations and sequencing of therapies can help prevent or delay the development of therapeutic drug resistance, and can be safely tolerated.

Detailed description:
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, the researchers believe providers 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, and in combination with carboplatin. The proposed sequencing is rationally designed, and based on each drug's distinct mechanisms of action as well as their toxicity profiles.

The 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.

To the researcher knowledge, no study has evaluated the use of rapidly cycling, non-cross reactive therapies for the treatment of mCRPC. The 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.

Primary objective is to evaluate the time to disease progression after completion of all modules of the rapidly-cycling, non-cross reactive regimen in patients with mCRPC. Secondary objectives are to evaluate overall survival, prostate-specific antigen (PSA) response rate with each treatment module, changes to alkaline phosphatase level, and assess safety of the rapidly-cycling, non-cross reactive regimen. Additional exploratory objective are to evaluate the correlation of a peripheral whole-blood RNA signature with clinical outcome measures during and after treatment, and to evaluate changes to AR-V7 expression in CTCs with different treatment modalities and clinical outcomes.

Arms:
arm 1: Prostate Cancer Rapidly cycling, Intensive, Non-Cross Reactive Therapy (PRINT) Rapidly cycling, consecutive treatment modules: 1. Abiraterone acetate; 2. Cabazitaxel + Carboplatin; 3. Enzalutamide + Radium-223

Interventions: intervention 1: Abiraterone acetate intervention 2: Prednisone intervention 3: Radium-223 dichloride intervention 4: cabazitaxel intervention 5: Carboplatin intervention 6: Enzalutamide
Intervention descriptions: intervention 1: Abiraterone acetate 1000 mg PO daily intervention 2: 5 mg PO twice a day intervention 3: 50 kBq/kg IV monthly intervention 4: 25 mg/m2 IV every 3 weeks intervention 5: Carboplatin AUC 4 IV every 3 weeks intervention 6: 160 mg PO daily

Protocol document:
Prot_SAP_000.pdf: 
 
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 
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(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 
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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 


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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 
 
 


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(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 
 
 


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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.   


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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). 
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. 
 
 
 


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(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. 


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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). 
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 


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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). 
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]. 


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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). 
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 


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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). 
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 


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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). 
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. 
 


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(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 


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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). 
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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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). 
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. 


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). 
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 


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). 
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. 
 


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). 
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 


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). 
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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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). 
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 


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). 
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 


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). 
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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The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
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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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The radium-223 values in this protocol have been revised as per the United States (US) National Institute of Standards and Technology 
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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, 


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). 
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. 
 
12. References 
1. 
de Bono, J.S., et al., Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-
resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. 
Lancet, 2010. 376(9747): p. 1147-54. 
2. 
de Bono, J.S., et al., Abiraterone and increased survival in metastatic prostate cancer. N Engl J 
Med, 2011. 364(21): p. 1995-2005. 
3. 
Ryan, C.J., et al., Abiraterone in metastatic prostate cancer without previous chemotherapy. N 
Engl J Med, 2013. 368(2): p. 138-48. 
4. 
Scher, H.I., et al., Increased survival with enzalutamide in prostate cancer after chemotherapy. N 
Engl J Med, 2012. 367(13): p. 1187-97. 
5. 
Kantoff, P.W., et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl 
J Med, 2010. 363(5): p. 411-22. 
6. 
Parker, C., et al., Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J 
Med, 2013. 369(3): p. 213-23. 
7. 
Beer, T.M., et al., Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N Engl J 
Med, 2014. 
8. 
Cheng, L., et al., Allelic imbalance in the clonal evolution of prostate carcinoma. Cancer, 1999. 
85(9): p. 2017-22. 
9. 
Mitsiades, N., et al., Distinct patterns of dysregulated expression of enzymes involved in 
androgen synthesis and metabolism in metastatic prostate cancer tumors. Cancer Res, 2012. 
72(23): p. 6142-52. 
10. 
Kantarjian, H.M., et al., Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult 
acute lymphocytic leukemia. J Clin Oncol, 2000. 18(3): p. 547-61. 
11. 
Thomas, D.A., et al., Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood, 
2004. 104(6): p. 1624-30. 
12. 
Horning, S.J., et al., Assessment of the stanford V regimen and consolidative radiotherapy for 
bulky and advanced Hodgkin's disease: Eastern Cooperative Oncology Group pilot study E1492. J 
Clin Oncol, 2000. 18(5): p. 972-80. 
13. 
Cheng, L., et al., Evidence of independent origin of multiple tumors from patients with prostate 
cancer. J Natl Cancer Inst, 1998. 90(3): p. 233-7. 
14. 
Macintosh, C.A., et al., Precise microdissection of human prostate cancers reveals genotypic 
heterogeneity. Cancer Res, 1998. 58(1): p. 23-8. 
15. 
Liu, W., et al., Copy number analysis indicates monoclonal origin of lethal metastatic prostate 
cancer. Nat Med, 2009. 15(5): p. 559-65. 


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). 
41
16. 
Madan, R.A., et al., Overcoming chemotherapy resistance in prostate cancer. Clin Cancer Res, 
2011. 17(12): p. 3892-902. 
17. 
Brown, E.M. and D. Nathwani, Antibiotic cycling or rotation: a systematic review of the evidence 
of efficacy. J Antimicrob Chemother, 2005. 55(1): p. 6-9. 
18. 
Schellhammer, P.F., et al., Lower baseline prostate-specific antigen is associated with a greater 
overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma 
Treatment (IMPACT) trial. Urology, 2013. 81(6): p. 1297-302. 
19. 
Beer, T.M., et al., Enzalutamide in men with chemotherapy-naive metastatic prostate cancer 
(mCRPC): Results of phase III PREVAIL study. J Clin Oncol, 2014. 32(suppl 4; abstr LBA1^). 
20. 
Loriot, Y., et al., Antitumour activity of abiraterone acetate against metastatic castration-
resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol, 
2013. 24(7): p. 1807-12. 
21. 
Noonan, K.L., et al., Clinical activity of abiraterone acetate in patients with metastatic castration-
resistant prostate cancer progressing after enzalutamide. Ann Oncol, 2013. 24(7): p. 1802-7. 
22. 
Schrader, A.J., et al., Enzalutamide in castration-resistant prostate cancer patients progressing 
after docetaxel and abiraterone. Eur Urol, 2014. 65(1): p. 30-6. 
23. 
Cheng, H.H., et al., Activity of enzalutamide in men with metastatic castration-resistant prostate 
cancer is affected by prior treatment with abiraterone and/or docetaxel. Prostate Cancer 
Prostatic Dis, 2015. 18(2): p. 122-7. 
24. 
Schmid, S.C., et al., Enzalutamide after docetaxel and abiraterone therapy in metastatic 
castration-resistant prostate cancer. Adv Ther, 2014. 31(2): p. 234-41. 
25. 
Arora, V.K., et al., Glucocorticoid receptor confers resistance to antiandrogens by bypassing 
androgen receptor blockade. Cell, 2013. 155(6): p. 1309-22. 
26. 
van Soest, R.J., et al., Cross-resistance between taxanes and new hormonal agents abiraterone 
and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate 
cancer. Eur J Cancer, 2013. 49(18): p. 3821-30. 
27. 
Mezynski, J., et al., Antitumour activity of docetaxel following treatment with the CYP17A1 
inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol, 2012. 23(11): p. 2943-7. 
28. 
Schweizer, M.T., et al., The Influence of Prior Abiraterone Treatment on the Clinical Activity of 
Docetaxel in Men with Metastatic Castration-resistant Prostate Cancer. Eur Urol, 2014. 
29. 
van Soest, R.J., et al., Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between 
Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer. Eur 
Urol, 2014. 
30. 
Azarenko, O., et al., Antiproliferative mechanism of action of the novel taxane cabazitaxel as 
compared with the parent compound docetaxel in MCF7 breast cancer cells. Mol Cancer Ther, 
2014. 13(8): p. 2092-103. 
31. 
Oh, W.K., M.H. Tay, and J. Huang, Is there a role for platinum chemotherapy in the treatment of 
patients with hormone-refractory prostate cancer? Cancer, 2007. 109(3): p. 477-86. 
32. 
Nakabayashi, M., et al., Response to docetaxel/carboplatin-based chemotherapy as first- and 
second-line therapy in patients with metastatic hormone-refractory prostate cancer. BJU Int, 
2008. 101(3): p. 308-12. 
33. 
Ross, R.W., et al., A phase 2 study of carboplatin plus docetaxel in men with metastatic 
hormone-refractory prostate cancer who are refractory to docetaxel. Cancer, 2008. 112(3): p. 
521-6. 
34. 
Regan, M.M., et al., Efficacy of carboplatin-taxane combinations in the management of 
castration-resistant prostate cancer: a pooled analysis of seven prospective clinical trials. Ann 
Oncol, 2010. 21(2): p. 312-8. 


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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). 
42
35. 
Corn, P.G., et al., A randomized phase I/II study to examine the contribution of carboplatin to 
cabazitaxel for the treatment of men with metastatic castration-resistant prostate cancer 
(mCRPC) with and without anaplastic features. J Clin Oncol, 2014. 32(suppl 4; abstr 148). 
36. 
Corn, P.G., et al., A multi-institutional randomized phase II study (NCT01505868) of cabazitaxel 
(CAB) plus or minus carboplatin (CARB) in men with metastatic castration-resistant prostate 
cancer (mCRPC). J Clin Oncol, 2015. 33(suppl; abstr 5010). 
37. 
Ross, R.W., et al., A whole-blood RNA transcript-based prognostic model in men with castration-
resistant prostate cancer: a prospective study. Lancet Oncol, 2012. 13(11): p. 1105-13. 
38. 
Hu, R., et al., Ligand-independent androgen receptor variants derived from splicing of cryptic 
exons signify hormone-refractory prostate cancer. Cancer Res, 2009. 69(1): p. 16-22. 
39. 
Antonarakis, E.S., et al., AR-V7 and resistance to enzalutamide and abiraterone in prostate 
cancer. N Engl J Med, 2014. 371(11): p. 1028-38. 
40. 
Scher, H.I., et al., Design and end points of clinical trials for patients with progressive prostate 
cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical 
Trials Working Group. J Clin Oncol, 2008. 26(7): p. 1148-59. 
41. 
Eisenberger, M., et al., Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m2) 
and the Currently Approved Dose (25 mg/m2) in Postdocetaxel Patients With Metastatic 
Castration-Resistant Prostate Cancer-PROSELICA. J Clin Oncol, 2017. 35(28): p. 3198-3206. 
42. 
Rowinsky, E.K., et al., Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin 
Oncol, 1991. 9(9): p. 1692-703. 
43. 
Cessna, J.T. and B.E. Zimmerman, Standardization of radium-223 by liquid scintillation counting. 
Appl Radiat Isot, 2010. 68(7-8): p. 1523-8. 
44. 
Zimmerman, B., et al., Revision of the NIST Standard for 223Ra: New Measurements and Review 
of 2008 Data. J Res Natl Inst Stand Technol, 2015. 120: p. 37-57. 
45. 
Beer, T.M., et al., Intermittent chemotherapy in patients with metastatic androgen-independent 
prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose 
calcitriol plus docetaxel with placebo plus docetaxel. Cancer, 2008. 112(2): p. 326-30. 
46. 
Cantor, A., SAS survival analysis techniques for medical research. 2nd edition. ed. 2003, Cary, 
North Carolina,: SAS Institute, Inc. viii, 230p. 
47. 
Lawless, J.F., Statistical models and methods for lifetime data. 2nd ed. Wiley series in probability 
and statistics. 2003, Hoboken, N.J.: Wiley-Interscience. xx, 630 p. 
48. 
Wolff, J.M., et al., Efficacy of skeletal alkaline phosphatase and prostate-specific antigen in the 
diagnosis of bone metastasis in cancer of the prostate. Urol Int, 1998. 61(1): p. 12-6. 
49. 
Sonpavde, G., et al., Serum alkaline phosphatase changes predict survival independent of PSA 
changes in men with castration-resistant prostate cancer and bone metastasis receiving 
chemotherapy. Urol Oncol, 2012. 30(5): p. 607-13. 
 

ICF_001.pdf: 
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


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
Page 1 of 28 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939 
Form Version Date: 05/22/2019 
This Section For IRB Official Use Only
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE 
 
Rev. 1/20/16
IRB Form HRP-502a
TITLE OF RESEARCH STUDY: 
Title: Prostate Cancer Intensive, Non-Cross Reactive Therapy (PRINT) for CRPC 
PRINCIPAL INVESTIGATOR (HEAD RESEARCHER) NAME AND CONTACT INFORMATION: 
Name: Bobby Liaw, M.D. 
Physical Address: Mount Sinai Downtown Chelsea Center, 
, New York, NY 10011 
Mailing Address: Mount Sinai Downtown Chelsea Center, 
, New York, NY 10011 
Phone: 212-604-6010 
Name: William Oh, M.D. 
Physical Address: Ruttenberg Treatment Center, 
 
, New York, NY 10029 
Mailing Address: One Gustave L. Levy Place, Box 1128, New York, NY 10029 
Phone: 212-659-5429 
WHAT IS A RESEARCH STUDY? 
A research study is when scientists try to answer a question about something that we don’t know 
enough about.  Participating may not help you or others.   
People volunteer to be in a research study.  The decision about whether or not to take part is totally 
up to you. You can also agree to take part now and later change your mind. Whatever you decide is 
okay.  It will not affect your ability to get medical care within the Mount Sinai Health System.   
Someone will explain this research study to you. Feel free to ask all the questions you want before 
you decide.  Any new information that develops during this research study that might make you 
change your mind about participating will be given to you promptly. 
Basic information about this study will appear on the website http://www.ClinicalTrials.gov.  There are 
a few reasons for this:  the National Institutes of Health (NIH) encourages all researchers to post their 
research; some medical journals only accept articles if the research was posted on the website; and, 
for research studies the U.S. Food and Drug Administration (FDA) calls "applicable clinical trials” a 
description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
PURPOSE OF THIS RESEARCH STUDY: 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
Page 2 of 28 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939 
Form Version Date: 05/22/2019 
This Section For IRB Official Use Only
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE 
 
Rev. 1/20/16
IRB Form HRP-502a
The purpose of this study is to better understand if cycling between different combinations of prostate 
cancer treatments already approved by the United States Food and Drug Administration (FDA) can 
help us achieve better long-term control of the disease.  While many new prostate cancer drugs have 
come out in recent years, the way that most oncologists are treating prostate cancer is to stay with 
one drug until it no longer works, then switch to a different one.  This means that once the disease 
has become resistant to that drug, all subsequent treatments will need to be able to overcome that 
resistance in order to be effective.  It is easier to develop drug resistance to a single drug as 
compared to a combination of drugs, since the likelihood of cancer cells forming resistance against 
two or more drugs simultaneously is less.  By switching between different combinations of active 
treatments before prostate cancer has a chance to develop resistance, we hope to be able to have 
better long-term control of the disease. 
Abiraterone acetate (Zytiga), cabazitaxel (Jevtana), enzalutamide (Xtandi), and radium-223 dichloride 
(Xofigo) have all been FDA approved for the treatment of metastatic prostate cancer that has 
progressed despite first line androgen deprivation therapy.  Carboplatin is a chemotherapy that is 
considered standard-of-care for the treatment of many different cancers, and has been well studied in 
prostate cancer.  Some studies have been designed to evaluate the effectiveness and safety of using 
some of these drugs in combinations with each other, but there have been no studies performed 
looking at the effects of switching between combinations, both good and bad. 
You are being given information about becoming a volunteer in a research study.  You may qualify to 
take part in this research study because you have prostate cancer that is no longer controlled by 
hormonal therapy alone. 
In this study you will receive treatment with all of the drugs listed above but in specific two-drug 
combinations, and in a specific sequence, as detailed below. 
Bayer is providing Radium-223 and Sanofi is providing Cabazitaxel.  Funds for conducting this 
research are provided by both Bayer and Sanofi.   
LENGTH OF TIME AND NUMBER OF PEOPLE EXPECTED TO PARTICIPATE 
Your participation in this research study is expected to last 2 years. 
The number of people expected to take part in this research study at the Icahn School of Medicine at 
Mount Sinai and the Mount Sinai Hospital is 32; Mount Sinai Downtown Chelsea Center 8.  The total 
number of people expected to take part and receive treatment on this research study is 40. 
DESCRIPTION OF WHAT’S INVOLVED: 
If you agree to participate in this research study, the following information describes what may be 
involved. 
This is a research study that will be conducted by the Icahn School of Medicine at Mount Sinai at 
Mount Sinai Hospital, Mount Sinai Downtown Chelsea Center, and Mount Sinai West.  Nearly all of 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
Page 3 of 28 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939 
Form Version Date: 05/22/2019 
This Section For IRB Official Use Only
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE 
 
Rev. 1/20/16
IRB Form HRP-502a
the research studies will take place at the cancer center where you see your oncologist.  You may 
have one additional blood test that will be analyzed by an outside laboratory that we will be partnering 
with (Epic Sciences, 9381 Judicial Drive, Suite 200, San Diego, CA 92121). 
We will review labs and radiology imaging to see if you are eligible for the study.  All parts of this 
evaluation have to be performed no longer than 8 weeks before starting on the study. If you are 
eligible and consent to the study, you will be asked to return to the clinic for your first study visit. 
During this visit, the following procedures will take place to establish your baseline status, your study 
doctor can give you more details about these tests: 

Complete medical history will be collected including information on your general health, past
surgeries and past treatments for prostate cancer and medications that you are taking (over
the counter medications, herbal remedies, vitamins, and supplements). (This procedure is
considered standard of care)

A complete physical examination including vital signs (blood pressure, heart rate, and
temperature), height and weight. (This procedure is considered standard of care)

To evaluate your disease you will undergo the following imaging studies (This procedure is
considered standard of care):
o
Computed Tomography (CT) scan – this test uses x-rays to look at tumors inside the
body. The CT scanner is typically a large, box like machine with a hole, or short tunnel,
in the center. You will lie on a narrow examination table that slides into and out of this
tunnel. The technologist begins by positioning you on the CT examination table, usually
lying flat on your back or possibly on your side or on your stomach. Straps and pillows
may be used to help you maintain the correct position and to hold still during the exam.
A CT scan takes approximately 30 minutes.  A contrast agent is a dye that mixes with
your blood to help make the images taken by the CT.  You will receive a contrast
agent, such as iodine, by an IV placed in your arm.
o
Bone scan – this test requires a radioactive tracer substance to be injected into a vein
in the arm, and then travels through the bloodstream and collects in your bones. A
special camera inside a machine is then used to take images of your bones.

Electrocardiogram (ECG) to measure the electrical activity of your heart. For this test, you will
be asked to lie down while 12 sticky pads are affixed to each of your arms and legs and to
your chest. The ECG will last about 20 minutes.  (This procedure is considered standard of
care)

Laboratory (blood) tests (This procedure is considered standard of care):
o
Hematology and chemistry analysis to evaluate how well your liver, kidneys, and other
organs are working (8ml or 1.5 teaspoons of blood will be taken)
o
Male hormone levels (Testosterone) and prostate-specific antigen (PSA) (5ml or 1
teaspoon of blood will be taken)

Research (blood) tests (These procedures are research specific, and are required as part of


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 4 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
the study): 
o A blood test to look at your genes and how they relate to prostate cancer (10 ml or 2.5 
teaspoons of blood will be taken).  This blood will be stored for future analysis. 
o A blood test to look for the presence of a specific mutation in prostate cancer cells that 
travel in the bloodstreams (10 ml or 2.5 teaspoons of blood will be taken).  This blood 
sample will be analyzed by the laboratory right away. 
o A tube of blood (10 ml or 2.5 teaspoons of blood will be taken) will be drawn and stored 
in a Streck Cell-Free tube for future studies only if the external laboratory that 
processes this particular blood sample is ready to receive it.  If not, this tube of blood 
will not be drawn. 
o These results will not be shared with you because they are preliminary results intended 
for research purposes only. They are not intended to manage or improve your 
healthcare. 
Our treatment regimen consists of three treatment modules that last 12 weeks each.  Everyone who 
participates in the study will go through all three modules in sequential order.  The treatment drugs 
(abiraterone acetate, cabazitaxel, carboplatin, enzalutamide, radium-223) and supportive drugs 
(prednisone, pegfilgrastim) that we are using in this study have all been well studied in advanced 
prostate cancer.  You will be receiving each drug at their approved dosing. 
The cancer treatments, lab tests, and imaging studies that you will receive within each module is 
detailed below: 
 
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 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 5 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
* only in patients with known bone metastases 
** deviation from schedule of ± 5 days allowed for IV therapies 
 
Module 1 (12 weeks): 
1. Abiraterone acetate 1000 mg (4 tablets of 250 mg each) by mouth once a day.  No food 
should be taken at least 2 hours before and 1 hour after taking abiraterone.  
2. Prednisone 5 mg (1 tablet of 5 mg) by mouth two times a day 
During this module, you will have blood draws every 2 weeks for the first 4 weeks, then every 4 weeks 
thereafter.  Follow up clinic visits will be scheduled for every 4 weeks during this first treatment 
module.  At the end of the 12 week treatment module, you will receive a CT scan and bone scan. 
 
At the end of this module, we will be able to determine whether or not your disease is responding to 
treatment with abiraterone acetate.  However, regardless of the type of response that you are having 
to these medications, we will be switching you to the treatment drugs in module 2 (below).  This 
switch in treatment is by design and is the novel approach that our clinical trial is studying. 
 
Module 2 (12 weeks): 
1. Cabazitaxel intravenously every 3 weeks 
2. Carboplatin intravenously every 3 weeks 
3. Pegfilgrastim by injection under the skin every 3 weeks 
4. Prednisone 5 mg (1 tablet of 5 mg) by mouth two times a day 
During this module, you will have office visits and blood draws every 3 weeks.  At the end of the 12 
weeks, you will receive a CT scan and bone scan.  The use of cabazitaxel and carboplatin in 
combination has been studied in phase II clinical trials and has been demonstrated to have 
acceptable and manageable side effects. 
 
At the end of this module, we will be able to determine whether or not your disease is responding to 
treatment with the combination of cabazitaxel and carboplatin.  However, regardless of the type of 
response that you are having to these medications, we will be switching you to the treatment drugs in 
module 3 (below).  This switch in treatment is by design and is the novel approach that our clinical trial 
is studying. 
 
Module 3 (12 weeks): 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 6 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
1. Enzalutamide 160 mg (4 tablets of 40 mg each) by mouth once a day 
2. Radium-223 dichloride intravenously every 4 weeks 
During this module, you will have blood draws every 2 weeks for the first 4 weeks, then every 4 weeks 
thereafter.  Follow up clinic visits will be scheduled every 4 weeks during this third treatment module.  
At the end of the 12 weeks, you will receive a CT scan and bone scan. 
After the completion of all three sequential modules of treatment, you will stop all prostate cancer 
treatments with the exception of a GnRH (gonadotropin releasing hormone) agonist or antagonist 
(e.g., leuprolide, goserelin, degarelix) and we will carefully monitor for any signs of prostate cancer 
progression though office visits every 4 weeks, checking blood work every 4 weeks, and repeating CT 
and bone scans every 12 weeks, until you have completed the first 12 weeks of surveillance.  After 
the first 12 weeks of surveillance, it will be arranged for you to have blood work checked every 4 
weeks, but office visits with the doctor will be every 12 weeks.  CT and bone scans will still be 
repeated every 12 weeks while you remain on surveillance.  
Your study doctor will continue to follow with you on the study for up to 24 months so that he/she may 
follow the progression of disease. 
If there is evidence of disease progression during the follow up period, your study doctor will decide 
with you what would be the best way to treat your disease.  Any of the drugs that you have received 
as part of the study will still be available to you for use.  At this time, the schedule of office visits, blood 
work, CT and bone scans, and treatment visits will then no longer be decided by the clinical trial, but 
will be arranged for you by your treating doctor based on what type of treatment is decided on next.    
Each office visit with your study doctor will usually take about an hour, and chemotherapy treatment 
sessions will be about 2 hours each.  Each time we draw blood, approximately 50 mL (10 tsp) will be 
taken. 
The chart below shows you what procedures will be done during the study. 
 
Baseline 
Treatment 
Post-
Treatment 
Surveillance 
Module 1 
Module 2 
Module 3 
Informed Consent 
Once 
 
 
 
 
Medical History 
Once 
 
 
 
 
Physical Examination 
Once 
Every 4 
weeks 
Every 3 
weeks 
Every 4 
weeks 
Every 4 
weeks for the 
first 12 
weeks, then 
every 12 
weeks 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 7 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
thereafter* 
Vital Signs/Weight 
Once 
Every 4 
weeks 
Every 3 
weeks 
Every 4 
weeks 
Every 4 
weeks for the 
first 12 
weeks, then 
every 12 
weeks 
thereafter* 
Performance Status 
Once 
Every 4 
weeks 
Every 3 
weeks 
Every 4 
weeks 
Every 4 
weeks for the 
first 12 
weeks, then 
every 12 
weeks 
thereafter* 
Complete blood count 
with differential 
Once 
Every 2 
weeks for the 
first 4 weeks, 
then every 4 
weeks 
thereafter 
Every 3 
weeks 
Every 2 
weeks for the 
first 4 weeks, 
then every 4 
weeks 
thereafter 
Every 4 
weeks* 
Blood test chemistries 
(CMP and LDH) 
Once 
Every 4 
weeks 
Every 3 
weeks 
Every 4 
weeks 
Every 4 
weeks* 
PSA (prostate 
specific antigen) 
Once 
Every 4 
weeks 
Every 3 
weeks 
Every 4 
weeks 
Every 4 
weeks* 
Testosterone 
Once 
Every 4 
weeks 
Every 3 
weeks 
Every 4 
weeks 
Every 4 
weeks* 
Electrocardiogram 
Once 
Every 4 
weeks 
 
 
 
Adverse Event  
Monitoring 
Once 
Every 4 
weeks 
Every 3 
weeks 
Every 4 
weeks 
Every 4 
weeks for the 
first 12 weeks 
CT scan of chest, 
abdomen, and pelvis 
Once 
Every 12 
weeks 
Every 12 
weeks 
Every 12 
weeks 
Every 12 
weeks* 
Bone Scan 
Once 
Every 12 
Every 12 
Every 12 
Every 12 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 8 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
weeks 
weeks 
weeks 
weeks* 
PAXgene Blood RNA 
tube (Research test) 
None 
At the start of 
the module 
At the start of 
the module 
At the start of 
the module 
At the start of 
surveillance, 
and again in 
12 weeks 
Streck Cell-Free DNA 
tube (Research 
test)** 
None 
At the start of 
the module** 
At the start of 
the module** 
At the start of 
the module** 
At the start of 
surveillance** 
*Until there is evidence of disease progression, after which the schedule of office visits, blood work, CT and 
bone scans, and treatment visits will be decided upon by your treating doctor. 
**Only if the external laboratory that performs this test is ready to receive this specimen.  If not, this tube will not 
be drawn. 
 
Since you are participating in a study that involves drugs or treatment with potential risks to a 
developing fetus, it is recommended that you use a condom and not father a child or donate sperm 
while you are taking the study drug. Also, it is recommended that you use a condom and not father a 
child and/or donate sperm for 90 days after you stop taking the study drug. This is because levels of 
the study drug may be present in the sperm and/or seminal fluid even after you stop taking the study 
drug. Continuing to use a condom and not donating sperm during this 90 day period may allow time 
for any study drug that is still present in sperm and/or seminal fluid to be eliminated from your body 
before you attempt to father a child or donate sperm. You are encouraged to tell your female 
partner(s) and/or their doctor(s) that you are participating in a clinical trial. 
 
Research blood studies 
There are research blood tests that are being performed as part of the study.  These tests are being 
performed to see if certain expressions of genes in your blood, or in the prostate cancer tumor cells 
that circulate in the bloodstream, have an effect on how your body and prostate cancer responds to 
certain prostate cancer treatments.  These labs will be collected in special study tubes called 
PAXgene Blood RNA tubes and Streck Cell-Free DNA blood collection tubes.  
In some cases, your sample will be destroyed and investigator will only keep study information 
collected/generated up to that point. There will be no direct benefit to you by taking part in this genetic 
research.  
These results will not be shared with you because they are preliminary results intended for research 
purposes only. They are not intended to manage or improve your healthcare. 
The physical risks and discomforts of giving this blood sample are the same as those for any blood 
sample taken from a vein. You may feel faint, experience mild pain, bruising, irritation or redness at 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 9 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
the site of puncture. In rare instances, you may develop an infection.  
The investigator has taken reasonable steps to keep your research information confidential. However, 
confidentiality cannot be guaranteed and there is a possibility that this could affect your insurance or 
employment. To protect your privacy, your samples will be coded and stored. Coding means that your 
specimens will be assigned an identifier such as a number so that the laboratory personnel analyzing 
your specimens will not know your identity. Your consent will limit the usage of your samples to the 
two tests described above.  In addition, your consent limits the storage time of your coded samples to 
a period of 15 years, at which time your samples will be destroyed.  The data that result from your 
samples may be stored for a time period of 15 years or even longer, if required by regulatory 
authorities. It may be necessary to send your coded samples and data to other countries and/or 
cooperating laboratories for analyses.  
If there is still any blood remaining after these two required tests, the researchers would like to ask 
your permission to keep blood specimens collected from you during this study to use them in future 
research studies.  They would also like to know your wishes about how they might use your 
specimens in future research studies. You should also know that it is possible that products may 
someday be developed with the help of your specimens, and that you will not receive any financial 
benefit that might come from the research. 
 
(1) Will you allow the researchers to store your specimens to use in future research studies? Please 
initial your choice: 
 
Yes________  No_________  If no, please stop here.  If yes, please continue to the next 
question. 
 
(2) Do you give the researchers permission to contact you in the future to collect additional 
information about you, discuss how your specimens might be used, or to discuss possible 
participation in another research project?  Please initial your choice: 
Yes_________ No__________ 
 
(3) Do you give the researchers permission to keep the specimens indefinitely and use them for future 
studies that are directly related to the purpose of the current study? Please initial your choice: 
 
Yes_________ No__________ 
 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 10 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
(4) Do you give the researchers permission to keep the specimens indefinitely and use them for future 
studies that are not related to the purpose of the current study (for example, a different area of 
research)?  Please initial your choice: 
Yes_________ No__________ 
 
(a) If the future research in a different area can be done without having to know that the 
specimens came from you personally, that will be done.  
(b) If the future research in a different area requires that it is known specifically who the 
specimens came from, then one of the following will be done: 
(i) If you allowed the researchers to contact you in the future, they will be able to 
contact you to explain why your specimen is needed and what will be done with it.  
Your permission will be asked to use your specimens in that research project.  
(ii) If you do not give permission to be contacted in the future, or if it is found that 
contacting you is not practical, for example, because you have moved, your specimens 
may still be used. Either all links to your identity will be removed from the specimens, 
or an Institutional Review Board will be asked for permission to use the specimens 
linked to your identity. The Institutional Review Board (IRB) is a committee of doctors 
and scientists and non-scientists and people not associated with this hospital or 
medical school whose job it is to protect people who participate in research. The IRB 
can give permission for researchers to use and share health information connected to 
specimens that are linked to people’s identities, but only if it determines that doing this 
will not be more than a minimal risk to people or their privacy. 
 
(5) Do you give permission to have portions of the specimens given to other researchers at Mount 
Sinai or other institutions for use in research that is either related or not related to the purpose of this 
study?  Please initial your choice: 
Yes_________ No__________ 
YOUR RESPONSIBILITIES IF YOU TAKE PART IN THIS RESEARCH: 
If you decide to take part in this research study you will be responsible for the following things: 
complying with requirements of the study, taking prescribed medications, use of birth control as stated 
below, and avoidance of certain medications and attendance at study visits.  
If you have a partner that is able to have children, you must be willing to use a barrier form of birth 
control during the study and for 1 week after you have taken the last dose of the study drug.  
 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 11 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
COSTS OR PAYMENTS THAT MAY RESULT FROM PARTICIPATION: 
Taking part in this research study may lead to added costs to you. You or your insurance company 
will be responsible for the costs of all items and services during the research study, which you would 
have received for your condition if you were not enrolled in this research study. You or your insurance 
company will also be responsible for the costs of all services that occur during the research study that 
your physician believes are medically necessary to treat you. You or your insurance company will not 
be responsible for the costs of the items and services associated with this research study, which are 
provided to you only for research purposes and not to treat your condition.  Some of the medications 
used in this study will need to be obtained through your insurance and you will be responsible for your 
prescription copayments. 
You will not be paid for participating in this research study.  You will have no rights to any patents or 
discoveries arising from this research, and you will receive no economic benefit.   
 POSSIBLE BENEFITS: 
It is important to know that you may not get any benefit from taking part in this research.  Others may 
not benefit either.  However, possible benefits may be improved long-term control of your prostate 
cancer.  Your disease may worsen while on this study due to the nature of the disease itself.  Future 
subjects with cancer may benefit from the results of this study. 
 REASONABLY FORESEEABLE RISKS AND DISCOMFORTS: 
The side effects of each of the treatment drugs used in this study have been well studied in large 
clinical trials.  You may have side effects from taking the study treatment (abiraterone acetate, 
radium-223 dichloride, cabazitaxel, carboplatin, enzalutamide, prednisone, pegfilgrastim). Everyone 
taking part in the study will be watched carefully for any side effects. However, doctors don’t know all 
the side effects that may happen. Side effects may be mild or very serious. Your health care team 
could give you medicines to treat the side effects. Many side effects caused by study medication may 
go away soon after you stop taking the study treatment. In some cases side effects can be serious, 
long lasting, or may never go away. It is not possible to tell which side effect will affect you or how 
mild or severe the side effect might become. We can only tell you what other people have 
experienced. Please talk with your study doctor about these side effects.  
You should tell your study doctor about any side effects, problems or unusual experiences that you 
have while taking part in this study. This may decrease the chance that the side effects continue or 
become worse. Sometimes there are other medications that your doctor can give you to make the 
side effects better or make you more comfortable. If severe side effects do develop, you and your 
doctor may decide it is in your best interest to stop taking part in the study.  
In patients with prostate cancer, it is often difficult to know if side effects after starting a new 
medication are due to the medication versus symptoms of the underlying cancer itself.  


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 12 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
Risks Associated with Abiraterone  
In clinical trials in which some patients were given abiraterone and other patients were given a 
placebo, some side effects occurred only slightly more commonly with abiraterone compared with 
placebo. At present, known side effects occurring in patients taking abiraterone include:  
Very common (≥ 1/10) [may occur in 10 or more subjects in 100]  
 
peripheral edema (swelling of the legs as a result of the body keeping too much fluid) 
 
hypokalaemia (low blood potassium, a mineral that helps regulate heart rate/function, fluid 
balance in the body and is needed for adequate body function) 
 
hypertension (high blood pressure) 
 
urinary tract infection 
 
fatigue (feeling tired) 
 
muscle or joint pain or stiffness 
 
constipation   
 
diarrhea 
 
nausea 
 
poor appetite 
 
elevated blood sugar 
 
urinary tract infection 
 
shortness of breath or cough 
 
hot flashes   
Common (≥ 1/100 to < 1/10) [may occur between 1 and 9 subjects in 100]  
 
alanine aminotransferase increased (an enzyme that measures the function of the liver)   
 
aspartate aminotransferase increased (an enzyme in the blood that measures the function of  
the liver)   
 
hypertriglyceridaemia (high blood levels of triglycerides, fatty molecule)   
 
cardiac failure (decreased function of the heart)   
 
congestive heart failure (a weakness of the heart that leads to a buildup of fluid in the lungs  
and surrounding body tissues)   
 
left ventricular dysfunction (inefficient pumping of the left side of the heart)   
 
ejection fraction decreased (inability of the heart to pump blood)   
 
angina pectoris (chest pain)   
 
arrhythmia (changes in the rhythm of the heart)   
 
atrial fibrillation (a fast and irregular heartbeat)   
 
tachycardia (rapid heartbeats)   
 
fractures (a break in the bone)   
 
dyspepsia (indigestion)   
 
hematuria (presence of blood in the urine)   


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 13 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
 
hyponatremia (low blood sodium)   
 
hypomagnesemia (low blood magnesium)   
 
hypocalcemia (low blood calcium)   
 
hypophosphatemia (low blood phosphorus)   
 
hypoalbuminemia (low blood albumin)   
 
pneumonia (infection of the lungs)   
 
sinusitis (infection of the sinuses)   
 
other infections   
 
creatinine increased (a protein that measures function of the kidneys)   
 
rash   
Uncommon (≥ 1/1,000 to < 1/100) [may occur between 1 and 9 subjects in 1000]  
 
adrenal insufficiency (disorder that occurs when the adrenal glands do not produce enough of 
certain hormones/ adrenal glands, located above the kidneys, do not produce adequate 
amounts of steroid hormones or if you stop your prednisone/prednisolone suddenly)  
Rare (Less than <.1% chance that this will happen)  
 
non-infectious pneumonitis (swelling and irritation of the lung)  
 
Risks Associated with Radium-223 
In clinical trials in which some patients were given radium-223 and other patients were given a 
placebo, some side effects occurred only slightly more commonly with radium-223 compared with 
placebo. At present, known side effects occurring in patients taking radium-223 include:  
Very common (≥ 1/10) [may occur in 10 or more subjects in 100]  
 
Peripheral edema (swelling of the legs as a result of the body keeping too much fluid) 
 
Nausea 
 
Diarrhea 
 
Vomiting 
 
Anemia (decreased red blood cell count) 
 
Lymphocytopenia (decreased number of lymphocytes, a particular type of white blood cell) 
 
Leukopenia (decreased white blood cell count) 
 
Thrombocytopenia (decreased platelet count) 
 
Neutropenia (decreased number of neutrophils, a particular type of white blood cell) 
Common (≥ 1/100 to < 1/10) [may occur between 1 and 9 subjects in 100]  
 
Dehydration 
 
Pancytopenia (decreased number of white blood cells, red blood cells, and platelets) 
 
Injection site reactions (swelling, pain, or redness of the skin where the drug is given) 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 14 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
 
Renal failure/insufficiency (decreased kidney functioning) 
Rare (Less than <0.1% chance that this will happen)  
 
Aplastic anemia (damage to the blood stem cells causing the inability to produce white blood 
cells, red blood cells, and platelets) 
 
Risks Associated with Enzalutamide 
In clinical trials in which some patients were given enzalutamide and other patients were given a 
placebo, some side effects occurred only slightly more commonly with enzalutamide compared with 
placebo. At present, known side effects occurring in patients taking enzalutamide include: 
Very common (≥ 1/10) [may occur in 10 or more subjects in 100]  
 
Peripheral edema (swelling of the legs as a result of the body keeping too much fluid) 
 
Hypertension (high blood pressure) 
 
Fatigue (tiredness) 
 
Falling 
 
Headache 
 
Dizziness 
 
Hot flash 
 
Weight loss 
 
Constipation 
 
Diarrhea 
 
Decreased appetite 
 
Neutropenia (decreased number of neutrophils, a particular type of white blood cell) 
 
Weakness 
 
Back pain 
 
Arthralgia (joint pain) 
 
Muscle or skeletal pain  
 
Upper respiratory tract infection 
 
Dyspnea (shortness of breath) 
Common (≥ 1/100 to < 1/10) [may occur between 1 and 9 subjects in 100]  
 
Insomnia (difficulty sleeping) 
 
Anxiety 
 
Paresthesia (abnormal sensation, typically pins and needles) 
 
Cauda equina syndrome (compression of the spinal cord nerve roots by a vertebral fracture or 
tumor) 
 
Spinal cord compression (compression of the spinal cord by a vertebral fracture or tumor) 
 
Altered mental status (confusion or delirium) 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 15 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
 
Hypoesthesia (decreased sense of touch or sensation) 
 
Hallucination 
 
Restless leg syndrome 
 
Pruritus (itchiness) 
 
Xeroderma (dry skin) 
 
Gynecomastia (breasts enlargement) 
 
Dysgeusia (changes to taste) 
 
Hematuria (blood in urine) 
 
Pollakiuria (increased urinary frequency) 
 
Thrombocytopenia (decreased platelet count) 
 
Increased serum bilirubin (an enzyme in the blood that measures the function of the liver)   
 
Infection 
 
Bone fracture (break) 
 
Stiffness 
 
Lower respiratory tract infection 
 
Epistaxis (nosebleed) 
 
Rare (Less than <0.1% chance that this will happen)  
 
Reversible posterior leukoencephalopathy syndrome (a syndrome characterized by headache, 
confusion, seizure, and visual loss, associated with characteristic findings of swelling seen on 
MRI of the brain) 
 
Seizure 
 
Risks Associated with Cabazitaxel 
Known side effects from clinical trials in which patients were given cabazitaxel include: 
Very common (≥ 1/10) [may occur in 10 or more subjects in 100]  
 
Fatigue (tiredness) 
 
Fever 
 
Diarrhea 
 
Nausea 
 
Vomiting 
 
Constipation 
 
Abdominal pain 
 
Anorexia (decreased appetite) 
 
Taste alteration (changes to taste) 
 
Anemia (decreased red blood cell count) 
 
Leukopenia (decreased white blood cell count) 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 16 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
 
Neutropenia (decreased number of neutrophils, a particular type of white blood cell) 
 
Thrombocytopenia (decreased platelet count) 
 
Weakness 
 
Back pain 
 
Peripheral neuropathy (damage to small nerves of hands and feet causing sensation of 
weakness, numbness, and pain) 
 
Arthralgia (joint pain) 
 
Hematuria (blood in urine) 
 
Dyspnea (shortness of breath) 
 
Cough 
 
Common (≥ 1/100 to < 1/10) [may occur between 1 and 9 subjects in 100]  
 
Peripheral edema (swelling of the legs as a result of the body keeping too much fluid) 
 
Arrhythmia (abnormal heart rhythm) 
 
Hypotension (low blood pressure) 
 
Dizziness 
 
Headache  
 
Pain 
 
Alopecia (loss of hair) 
 
Dehydration 
 
Dyspepsia (upset stomach) 
 
Weight loss 
 
Mucosal inflammation (inflammation of the inside lining of the gastrointestinal tract) 
 
Urinary tract infection 
 
Dysuria (discomfort with urination) 
 
Neutropenic fever (fever caused by infection due to having a suppressed immune system) 
 
Alanine aminotransferase increased (an enzyme in the blood that measures the function of the 
liver)   
 
Aspartate aminotransferase increased (an enzyme in the blood that measures the function of 
the liver)   
 
Bilirubin increased (an enzyme in the blood that measures the function of the liver)   
 
Muscle spasm 
Rare (Less than <0.1% chance that this will happen)  
 
Colitis (inflammation of the colon) 
 
Electrolyte imbalance (increase or decrease of electrolytes found in the blood, such as 
sodium, chloride, magnesium, potassium, and calcium) 
 
Enterocolitis (inflammation of the stomach and colon) 
 
Gastritis (inflammation of the stomach) 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 17 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
 
Gastrointestinal hemorrhage (bleeding from the gastrointestinal tract) 
 
Gastrointestinal perforation (a hole forming in the wall of the gastrointestinal tract) 
 
Hypersensitivity (allergic-type reactions, such as rash, redness, low blood pressure, and 
difficulty breathing) 
 
Intestinal obstruction (blockage of the gastrointestinal tract) 
 
Neutropenic enterocolitis (inflammation of the stomach and colon caused by suppressed 
immune system) 
 
Renal (kidney) failure 
 
Sepsis (severe infection) 
 
 
Risks Associated with Carboplatin 
Very common (≥ 1/10) [may occur in 10 or more subjects in 100]  
 
Pain 
 
Hyponatremia (low blood sodium, a mineral that helps regulate heart rate/function, fluid 
balance in the body, and is needed for adequate body function) 
 
Hypomagnesemia (low blood magnesium, a mineral that helps regulate heart rate/function, 
fluid balance in the body and is needed for adequate body function) 
 
Hypocalcemia (low blood calcium, a mineral that helps regulate heart rate/function, fluid 
balance in the body, and is needed for adequate body function) 
 
Hypokalemia (low blood potassium, a mineral that helps regulate heart rate/function, fluid 
balance in the body, and is needed for adequate body function) 
 
Vomiting 
 
Abdominal pain 
 
Nausea 
 
Bone marrow depression (decreased ability for the bone marrow to produce new white blood 
cells, red blood cells, and platelets) 
 
Leukopenia (decreased white blood cell count) 
 
Neutropenia (decreased number of neutrophils, a particular type of white blood cell) 
 
Thrombocytopenia (decreased platelet count) 
 
Increased serum alkaline phosphatase (an enzyme in the blood that measures the function of 
the liver)   
 
Increased aspartate aminotransferase (an enzyme in the blood that measures the function of 
the liver) 
 
Hypersensitivity (allergic-type reactions, such as rash, redness, low blood pressure, and 
difficulty breathing) 
 
Weakness 
 
Decreased creatinine clearance (decreased kidney function) 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 18 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
Common (≥ 1/100 to < 1/10) [may occur between 1 and 9 subjects in 100]  
 
Peripheral neuropathy 
 
Neurotoxicity 
 
Alopecia (loss of hair) 
 
Constipation 
 
Diarrhea 
 
Dysgeusia (changes to taste) 
 
Mucositis (inflammation to lining of mouth and throat) 
 
Stomatitis (inflammation of mouth and lips) 
 
Bleeding complications 
 
Hemorrhage (bleeding) 
 
Increased serum bilirubin (an enzyme in the blood that measures the function of the liver) 
 
Infection 
 
Visual disturbance (changes to vision) 
 
Ototoxicity (changes to hearing such as decreased hearing or ringing in ears) 
Rare (Less than <0.1% chance that this will happen)  
 
Anaphylaxis (severe allergic reaction) 
 
Risks Associated with Prednisone 
 
High blood pressure 
 
High blood glucose (sugar) level 
 
Fluid retention 
 
Increased intra-ocular (eye) pressure or glaucoma 
 
Menstrual irregularities 
 
Worsening of pre-existing abnormal thyroid hormone levels 
 
Stomach bleeding, indigestion 
 
Muscle weakness and muscle loss 
 
Osteoporosis 
 
Easy bruising 
 
Thin skin 
 
Weakens body’s ability to fight off infection, and can make infections hard to diagnose or treat 
 
Headache 
 
Mood swings 
 
Personality changes 
 
Severe depression 
 
Increased intra-cranial pressure (pressure increased in head/skull) 
 
Cataracts 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 19 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
 
Vertigo 
 
Hallucinations 
 
Congestive heart failure (worsening heart function) in patients with pre-existing heart disease 
 
Muscle tears or bone fractures 
 
Insomnia (wakefulness) 
 
Cushing’s syndrome includes weight gain, a “moon-faced” appearance, thin fragile skin, 
muscle weakness, brittle bones and purplish stripe marks on the skin. 
 
Adrenal insufficiency (loss of function of adrenal glands that normally help maintain blood 
pressure, balance minerals and fluid in your body) 
 
Sudden stoppage of prednisone/prednisolone, may lead to tiredness, very low blood pressure, 
very low blood sugar, and abnormalities of the minerals in bloodstream. 
 
Risks Associated with Pegfilgrastim 
Very common (≥ 1/10) [may occur in 10 or more subjects in 100]  
 
Ostealgia (bone pain)  
Common (≥ 1/100 to < 1/10) [may occur between 1 and 9 subjects in 100]  
 
Limb pain 
Rare (Less than <0.1% chance that this will happen)  
 
Splenic rupture (medical emergency where spleen swells and bursts) 
 
Acute respiratory distress syndrome (life threatening lung condition that prevents enough 
oxygen from getting to the lungs and into the blood) 
 
Anaphylaxis (serious allergic reaction) 
 
Leukocytosis (increased white blood cell count) 
 
Fever 
 
Flushing 
 
Polyarthralgia (joint pain) 
 
Chest pain 
 
Musculoskeletal pain (muscle and skeletal pain) 
 
Urticaria (hives) 
 
Weakness 
 
Splenomegaly (enlarged spleen) 
 
Allergies to acrylics.  (the on-body injector for pegfilgrastim uses acrylic adhesive) 
 
Glomerulonephritis (inflammation of the kidney) 
 
Capillary leak syndrome (rare disorder characterized by leakage of plasma and other blood 
components from blood vessels into neighboring body cavities and muscles) 
 
Severe sickle cell crisis (for people with a history of sickle cell disease, this medication can 
cause severe and sometimes fatal sickle cell crises) 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 20 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
 
Injection site reaction (redness, irritation, or swelling at the site of injection) 
 
Periorbital edema (swelling or retention of water around the eyes) 
 
Sweet's syndrome (rare skin condition marked by fever and painful skin lesions that appear 
mainly on your arms, neck, face and back) 
 
Risks Associated with Imaging Scans 
You will have radiation-based procedures or examinations that are part of the regular care for your 
condition and you will have them whether or not you participate in this research.  You will not be 
exposed to any additional radiation because you are participating in this research. 
You will be exposed to radiation from the CT scans and Bone scans, and from the MUGA done to test 
how well your heart is pumping.  The following information will help you understand how much 
radiation, and the risks from the radiation.  Radiation is measured in units called “millisieverts” (mSv.) 
We are all exposed to radiation on a daily basis from natural sources such as the sun, or artificial 
sources such as computer screens. This exposure is called “background exposure”. A person living in 
the US gets 6.2 mSv of background exposure each year. The United States Nuclear Regulatory 
Commission (NRC) sets recommendations for additional radiation exposure. For the general public, 
the yearly limit is 1 mSv. For people who work with radiation, such as X-ray technicians, the yearly 
limit is 50 mSv.   
One CT of the chest, abdomen, and pelvis exposes you to 17 mSv of radiation.  One bone scan 
exposes you to 5.3 mSv.  
In the first year of the study you will have one CT of the chest, abdomen and pelvis and one bone 
scan every 3 months. The total exposure from these tests in the first year is 89.2 mSv.  In the second 
year of the study you will have one CT of the chest abdomen and pelvis and one bone scan every 3 
months, for a total exposure of 89.2 mSv for the second year.  
The radiation exposure for each year of the study is greater than the background exposure and 
greater than the NRC yearly limits for people who work with radiation (50 mSv).  However, the 
investigators feel that this level or exposure is acceptable because it is no greater than the amount of 
radiation that you would receive from standard medical monitoring of your condition. The study team 
will discuss radiation exposure with you.  
The study team will always try to minimize your exposure to radiation by whenever possible using 
tests that involve the least amount of exposure possible. The radiation from the tests and treatments 
in this study would be in addition to any radiation you might receive from other medical tests or 
treatments. If you are going to have any other tests or treatments that involve radiation, please inform 
the study team.  
Blood Draws 
The risks of having blood drawn include, pain, bruising, and rarely, infection. Blood will be drawn by 
experienced technicians, and whenever possible it will be obtained at a time when blood is being 
obtained for other tests your doctor has ordered.  


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 21 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
Economic risks 
These include having to pay money out of pocket for copayment on certain drugs required for this 
study, and potentially needing to miss work for study and treatment visits. 
Genetic Risks 
There is a Federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this 
law makes it illegal for health insurance companies, group health plans, and most employers of over 
15 people to discriminate against you based on your genetic information. However, it does not protect 
you against discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. 
Privacy risks 
There always exists the potential for loss of private information; however, there are procedures in 
place to minimize this risk.  
Unknown Risks 
In addition to these risks, this research may hurt you in ways that are not known. The unknown risks 
might be minor or might be major (death).  
OTHER POSSIBLE OPTIONS TO CONSIDER: 
You may decide not to take part in this research study without any penalty.  The choice is totally up to 
you. 
Instead of being in this research study, your choices may include:  
 
Getting treatment or care for your cancer without being in a study. 
 
Receiving abiraterone (Zytiga) without being in the study.  Abiraterone is currently approved by 
the FDA for patients with metastatic prostate cancer that has progressed despite hormonal 
therapy. 
 
Receiving radium-223 dichloride without being in the study.  Radium-223 is currently approved 
by the FDA for patients with prostate cancer with bone metastasis that has progressed despite 
hormonal therapy 
 
Receiving enzalutamide (Xtandi) without being in the study.  Enzalutamide is currently 
approved by the FDA for patients with metastatic prostate cancer that has progressed despite 
hormonal therapy. 
 
Receiving docetaxel (Taxotere).  Docetaxel is a chemotherapy drug approved by the FDA for 
the treatment of metastatic prostate cancer that has progressed despite hormonal therapy.  
The risks of treatment are lowering of the blood counts, infection, fatigue, and numbness of the 
fingers and toes. 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 22 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
 
Receiving sipuleucel-T (Provenge).   Sipuleucel T is approved by the FDA for metastatic 
prostate cancer that has progressed despite hormonal therapy.  The risks of this treatment are 
chills, fever, fatigue, nausea, and headahce which usually occur within the first few days of 
treatment.  
 
Taking part in another study, if one will become available  
 
Getting no treatment  
Talk to your study doctor about your choices before you decide if you will take part in this study.  
IN CASE OF INJURY DURING THIS RESEARCH STUDY: 
If you are injured or made sick from taking part in this research study, medical care will be provided. 
Generally, this care will be billed to you or your insurance in the ordinary manner and you will be 
responsible for all treatment costs not covered by your insurance, including deductibles, co-payments 
and coinsurance.  This does not prevent you from seeking payment for injury related to malpractice or 
negligence. Contact the investigator for more information. 
If you are injured or become ill from the Study Drug or from one of the Study tests or procedures, you 
or your insurance company will be billed for the costs of treatment if the injury or illness is due to an 
underlying medical condition or from the normal progression of your cancer. Bayer and Sanofi, who is 
providing funding support and study product, will not pay for any costs associated with patient 
injury/medical costs.  
Even if you sign this form, you have not given up any of your legal rights and could choose to file a 
claim. 
 ENDING PARTICIPATION IN THE RESEARCH STUDY: 
You may stop taking part in this research study at any time without any penalty. This will not affect 
your ability to receive medical care at any of the Mount Sinai Health System hospitals or to receive 
any benefits to which you are otherwise entitled. 
If you decide to stop being in the research study, please contact the Principal Investigator or the 
research staff.    
If you decide to stop being in the research study, the following may occur: you may stop experiencing 
benefit from the treatment regimen, and there may be possibility for your disease to progress.  
If you stop being in the research study, already collected information may not be removed from the 
research study database and will continue to be used to complete the research analysis.  You may be 
asked whether the investigator can collect information from your routine medical care. If you agree, 
this data will be handled the same as research data.  Some of the labs drawn as part of the study are 
used for research, you may be asked whether these labs can still be drawn during routine blood 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 23 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
draws for your ongoing medical care.  Samples that have already been collected cannot be withdrawn 
or destroyed, but are anonymized. 
You may also withdraw your permission for the use and disclosure of any of your protected 
information for research, but you must do so in writing to the Principal Investigator at the address on 
the first page. Even if you withdraw your permission, the Principal Investigator for the research study 
may still use the information that was already collected if that information is necessary to complete the 
research study. Your health information may still be used or shared after you withdraw your 
authorization if you have an adverse event (a bad effect) from participating in the research study. 
Withdrawal without your consent: The study doctor, the sponsor or the institution may stop your 
involvement in this research study at any time without your consent. This may be because the 
research study is being stopped, the instructions of the study team have not been followed, the 
investigator believes it is in your best interest, or for any other reason. If specimens or data have been 
stored as part of the research study, they too can be destroyed without your consent.  More possible 
reasons for removal from the study include initiation of other active prostate cancer treatments without 
study permission. 
CONTACT PERSON(S): 
If you have any questions, concerns, or complaints at any time about this research, or you think the 
research has hurt you, please contact the office of the research team and/or the Principal Investigator 
at phone number: 212-604-6010. 
If you experience an emergency during your participation in this research, please call 911 or go to the 
emergency room. 
This research has been reviewed and approved by an Institutional Review Board. You may reach a 
representative of the Program for Protection of Human Subjects at the Icahn School of Medicine at 
Mount Sinai at telephone number (212) 824-8200 during standard work hours for any of the reasons 
listed below. This office will direct your call to the right person within the Mount Sinai Health System: 
 
Your questions, concerns, or complaints are not being answered by the research team. 
 
You cannot reach the research team. 
 
You are not comfortable talking to the research team. 
 
You have questions about your rights as a research subject. 
 
You want to get information or provide input about this research. 
DISCLOSURE OF FINANCIAL INTERESTS: 
Sometimes, physicians/researchers receive payments for consulting or similar work performed for 
industry.  Effective September 2014 Mount Sinai reviews only payments to an individual totaling more 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 24 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
than $5,000 a year per entity when determining potential conflicts of interest.  If you have questions 
regarding industry relationships, we encourage you to talk your physician/researcher or visit our 
website at http://icahn.mssm.edu/ where Mount Sinai publicly discloses the industry relationships of 
our faculty.  
Dr. William Oh (a Co-Investigator in this study) receives financial compensation as an advisory board 
member or consultant for Bayer (a co-sponsor of this study and manufacturer of the study drug 
Radium-223), Sanofi-Aventis (a co-sponsor of this study and manufacturer of study drug cabazitaxel), 
and Janssen Biotech, Inc. (manufacturer of the study drug abiraterone). 
 
 
MAINTAINING CONFIDENTIALITY – HIPAA AUTHORIZATION: 
As you take part in this research project it will be necessary for the research team and others to use 
and share some of your private protected health information. Consistent with the federal Health 
Insurance Portability and Accountability Act (HIPAA), we are asking your permission to receive, use 
and share that information. 
What protected health information is collected and used in this study, and might also be disclosed 
(shared) with others? 
As part of this research project, the research team at the hospital(s) involved in the research will 
collect your name, address, telephone/fax numbers, birth date, hospital admission or discharge dates, 
email address, social security number, medical record number, health plan numbers, biometric 
identifiers, and photographic images.  Only if applicable, date of death will be recorded.   
The researchers will also get information from your medical records from your outpatient doctors, 
including your primary care doctor and any specialists you are seeing, and any hospital admissions.   
During the study the researchers will gather information by: 
 
taking a medical history (includes current and past medications or therapies, illnesses, 
conditions or symptoms, family medical history, allergies, etc.) 
 
doing a physical examination that generally also includes blood pressure reading, heart rate, 
breathing rate and temperature 
 
completing the tests, procedures, questionnaires and interviews explained in the description 
section of this consent. 
 
reviewing genetic tests 
 
Why is your protected health information being used? 
Your personal contact information is important to be able to contact you during the study. Your health 
information and the results of any tests and procedures being collected as part of this research study 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 25 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
will be used for the purpose of this study as explained earlier in this consent form. The results of this 
study could be published or presented at scientific meetings, lectures, or other events, but would not 
include any information that would let others know who you are, unless you give separate permission 
to do so. 
The Principal Investigator may also use and share the results of these tests and procedures to treat 
you in collaboration with others in the Mount Sinai Health System.  
The research team and other authorized members of The Mount Sinai Health System (“Mount Sinai”) 
workforce may use and share your information to ensure that the research meets legal, institutional or 
accreditation requirements. For example, the School’s Program for the Protection of Human Subjects 
is responsible for overseeing research on human subjects, and may need to see your information. If 
you receive any payments for taking part in this study, the Mount Sinai Finance Department may need 
your name, address, social security number, payment amount, and related information for tax 
reporting purposes.  If the research team uncovers abuse, neglect, or reportable diseases, this 
information may be disclosed to appropriate authorities.  
Who, outside Mount Sinai, might receive your protected health information? 
As part of the study, the Principal Investigator, study team and others in the Mount Sinai workforce 
may disclose your protected health information, including the results of the research study tests and 
procedures, to the following people or organizations: (It is possible that there may be changes to the 
list during this research study; you may request an up-to-date list at any time by contacting the 
Principal Investigator.) 
- 
Other collaborating research center(s) and their associated research/clinical staff who are 
working with the investigators on this project: The Icahn School of Medicine at Mount Sinai 
and the Mount Sinai Hospital, Mount Sinai Beth Israel, and Mount Sinai West 
- 
Research data coordinating office and/or their representative(s) who will be responsible for 
collecting results and findings from all the centers: Mount Sinai 
- 
The commercial sponsor and/or their representative (who will use the results for 
submissions to the Food and Drug Administration): Bayer, Sanofi 
- 
A Data Safety Monitoring Board or other committee that will monitor the study on an 
ongoing basis for safety. 
- 
The United States Food and Drug Administration 
- 
The United States Department of Health and Human Services and the Office of Human 
Research Protection. 
In all disclosures outside of Mount Sinai, you will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier unless disclosure of the direct 
identifier is required by law. Some records and information disclosed may be identified with a unique 
code number. The Principal Investigator will ensure that the key to the code will be kept in a locked 
file, or will be securely stored electronically. The code will not be used to link the information back to 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 26 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
you without your permission, unless the law requires it, or rarely if the Institutional Review Board 
allows it after determining that there would be minimal risk to your privacy. It is possible that a sponsor 
or their representatives, a data coordinating office, a contract research organization, may come to 
inspect your records. Even if those records are identifiable when inspected, the information leaving 
the institution will be stripped of direct identifiers.  Additionally, when applicable, the monitors, 
auditors, the IRB, the Office of Human Subjects Protection (OHRP) of the Department of Health and 
Human Services as well as the Food and Drug Administration (FDA) will be granted direct access to 
your medical records for verification of the research procedures and data. OHRP and FDA are 
authorized to remove information with identifiers if necessary to complete their task. By signing this 
document you are authorizing this access. We may publish the results of this research. However, we 
will keep your name and other identifying information confidential. 
For how long will Mount Sinai be able to use or disclose your protected health information?  
Your authorization for use of your protected health information for this specific study does not expire. 
Will you be able to access your records? 
During your participation in this study, you will have access to your medical record and any study 
information that is part of that record. The investigator is not required to release to you research 
information that is not part of your medical record. 
Do you need to give us permission to obtain, use or share your health information? 
NO! If you decide not to let us obtain, use or share your health information you should not sign this 
form, and you will not be allowed to volunteer in the research study. If you do not sign, it will not affect 
your treatment, payment or enrollment in any health plans or affect your eligibility for benefits. 
Can you change your mind? 
You may withdraw your permission for the use and disclosure of any of your protected information for 
research, but you must do so in writing to the Principal Investigator at the address on the first page. 
Even if you withdraw your permission, the Principal Investigator for the research study may still use 
your protected information that was already collected if that information is necessary to complete the 
study. Your health information may still be used or shared after you withdraw your authorization if you 
should have an adverse event (a bad effect) from being in the study. If you withdraw your permission 
to use your protected health information for research that means you will also be withdrawn from the 
research study, but standard medical care and any other benefits to which you are entitled will not be 
affected. You can also tell us you want to withdraw from the research study at any time without 
canceling the Authorization to use your data. 
If you have not already received it, you will also be given The Hospital’s Notice of Privacy Practices 
that contains more information about how The Hospital uses and discloses your protected health 
information. 
It is important for you to understand that once information is disclosed to others outside Mount Sinai, 
the information may be re-disclosed and will no longer be covered by the federal privacy protection 
regulations. However, even if your information will no longer be protected by federal regulations, 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 27 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
where possible, Mount Sinai has entered into agreements with those who will receive your information 
to continue to protect your confidentiality. 
If as part of this research project your medical records are being reviewed, or a medical history is 
being taken, it is possible that HIV-related information may be revealed to the researchers.  If that is 
the case, the following information concerns you.  If this research does not involve any review of 
medical records or questions about your medical history or conditions, then the following section may 
be ignored.   
 
_________________________________________________________________________________ 
Notice Concerning HIV-Related Information 
If you are authorizing the release of HIV-related information, you should be aware that the recipient(s) is 
(are) prohibited from re-disclosing any HIV-related information without your authorization unless permitted 
to do so under federal or state law.  You also have a right to request a list of people who may receive or 
use your HIV-related information without authorization.  If you experience discrimination because of the 
release or disclosure of HIV-related information, you may contact the New York State Division of Human 
Rights at (888) 392-3644 or the New York City Commission on Human Rights at (212) 306-5070.  These 
agencies are responsible for protecting your rights. 
_____________________________________________________________________________________ 
 
 
 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai,  
Mount Sinai Beth Israel, Mount Sinai West  
 
Page 28 of 28 
 
 
Study ID #: GCO# 16-1593 (0001) and 16-1593 (0002)/ HSM# 16-00939  
 
 
 
 
Form Version Date: 05/22/2019 
 
This Section For IRB Official Use Only 
This Consent Document is approved for use by an Institutional Review Board (IRB) 
Form Approval Date: 
 
DO NOT SIGN AFTER THIS DATE  
 
Rev. 1/20/16 
IRB Form HRP-502a 
 
Signature Block for Capable Adult 
Your signature below documents your permission to take part in this research and to the use and 
disclosure of your protected health information. A signed and dated copy will be given to you. 
DO NOT SIGN THIS FORM AFTER THIS DATE  
 
 
 
 
Signature of subject 
 
Date  
 
 
 
Printed name of subject 
 
Time 
 [required if used for FDA 
documentation purposes] 
 
 
 
Person Explaining Study and Obtaining Consent  
 
 
 
Signature of person obtaining consent 
 
Date  
 
 
 
Printed name of person obtaining consent 
 
Time  
 
 
Witness Section: For use when a witness is required to observe the consent process,, 
document below (for example, subject is illiterate or visually impaired, or this accompanies a 
short form consent): 
My signature below documents that the information in the consent document and any other 
written information was accurately explained to, and apparently understood by, the subject, and 
that consent was freely given by the subject. 
 
 
 
Signature of witness to consent process 
 
Date  
 
 
 
Printed name of person witnessing consent process 
 
Time