Clinical trial NCT02218606
Conditions: Prostate Cancer
Keywords: Abiraterone Acetate CABAZITAXEL CASTRATION RESISTANT 14-046 Prostate Cancer Clinical Trials Consortium
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2014-08-01; Completion date: 2023-10-13
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to see what effects (good and bad) treatment with abiraterone acetate (an oral hormonal agent) and prednisone (a steroid) with and without cabazitaxel (a chemotherapy) have on the cancer and to find out more about whether specific laboratory tests on tumor are useful in predicting how the patient will respond to treatment.

Detailed description:

Arms: arm 1: Arm 1: Abiraterone acetate 1000 mg po daily + prednisone 5 mg po BID arm 2: Arm 2: Cabazitaxel 25 mg/m2 IV + abiraterone acetate 1000 mg po daily + prednisone 5 mg po BID
Interventions: intervention 1: Abiraterone acetate 1000 mg po daily intervention 2: Cabazitaxel 25 mg/m2 IV intervention 3: prednisone 5 mg po BID
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
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Cabazitaxel and Abiraterone Acetate 
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AN EXPLORATORY RANDOMIZED PHASE II MULTICENTER 
TRIAL OF ABIRATERONE ACETATE WITH OR WITHOUT 
CABAZITAXEL IN TREATMENT OF METASTATIC CASTRATION 
RESISTANT PROSTATE CANCER 
Prostate Cancer Clinical Trials Consortium, LLC (PCCTC) 
PCCTC LOI#: c12-108 
Lead Site: Memorial Sloan Kettering Cancer Center 
Sponsor: Memorial Sloan Kettering Cancer Center 
Principal Investigator 
Susan Slavin, MD, PhD 
Memorial Sloan Kettering Cancer Center 
Service Chief, Genitourinary Oncology Service 
1275 York Avenue 
New York, NY 10021 
Slovins@mskcc.org 
Statistician 
Susan Halabi, PhD 
Department of Biostatistics & 
Bioinformatics 
Duke University 
Duke Box 2717 
Durham, NC 27710 
Susan.halabi@duke.edu 
Co-Investigator 
William Kelly, D.O. 
Thomas Jefferson University Hospital 
Department of Medical Oncology 
1025 Walnut Street 
College Bldg., Suite 700 
Philadelphia, PA 19107 
Wm.Kevin.Kelly@jefferson.edu 
Correlative Science 
Karen Knudsen, PhD 
Professor of Cancer Biology, Urology, and Radiation 
Oncology, KCC 
233 10th Street, BLSB 1008 
Philadelphia, PA 19107 
Phone: 215-503-8573 
Karen.Knudsen@jefferson.edu 


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Pathology Collaborators 
Ruth Birbe, MD 
Thomas Jefferson University Hospital 
1325 10th St 
Main Building, Suite 285A 
Philadelphia PA 19107 
Rossitza Draganova-Tacheva, MD 
Thomas Jefferson University Hospital 
1325 10th St 
Main Building, Suite 285A 
Philadelphia PA 19107 
Participating Site(s) 
Principal Investigator 
Site's Role 
Thomas Jefferson University 
William Kelly, D.O. 
Data Collection and Specimen 
Analysis 
Duke University 
Susan Halabi, PhD 
Data Analysis 
Weill Cornell Medical Center 
Ana Molina, M.D. 
Data Collection 
Virginia Oncology Associates 
Mark Fleming, M.D. 
Data Collection 


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 STATEMENT The information in this document is provided to you as an investigator, potential investigator, consultant, or contractor, for review by you, your staff, and the appropriate InstitutionalReview Board or Ethics Committee. Byaccepting this document, you agree thattheinformation contained herein willnot be disclosedto others without written authorization from the lead site/sponsor, except to theextent necessaryto initiate the study or conduct study-relatedactivities.
 
Protocol Date: June 13, 2014 
Amended Version Date: October 17, 2016 
INVESTIGATOR'S APPROVAL OF PROTOCOL 
Title: AN EXPLORATORY RANDOMIZED PHASE ll MULTICENTER TRIAL OFABIRATERONEACETATE 
WITH OR WITHOUTCABAZITAXEL IN TREATMENT OF METASTATIC CASTRATION RESISTANT 
PROSTATE CANCER 
Principal Investigator Signature:  
 
Principal Investigator Print:  
 
Date:  
 


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Table of Contents 
1. 
INTRODUCTION, BACKGROUND AND RATIONALE .................................................................................... 6 
1.1 
Disease Background ................................................................................................................................................. 6 
1.2 
Background ................................................................................................................................................................ 6 
1.3 
Rationale ................................................................................................................................................................. 11 
2. 
OBJECTIVES ................................................................................................................................................. 13 
2.1 
Primary Objective ............................................................................................................................................... 13 
2.2 
Secondary Objectives ......................................................................................................................................... 13 
2.3 
Correlative Studies .............................................................................................................................................. 13 
3. 
PATIENT SELECTION .................................................................................................................................. 13 
3.1 
Inclusion Criteria ................................................................................................................................................. 13 
3.2 
Exclusion Criteria ................................................................................................................................................. 15 
3.3 
Prohibited Concomitant Medications ............................................................................................................. 16 
4. 
ENROLLMENT PLAN AND SUBJECT REGISTRATION ................................................................................ 16 
4.1 
Enrollment Plan................................................................................................................................................... 16 
4.2 
Registration Procedure ....................................................................................................................................... 17 
5. 
RANDOMIZATION ....................................................................................................................................... 18 
6. 
STUDY ASSESSMENTS BY VISITS ................................................................................................................. 19 
6.1 
Screening/Pretreatment Assessment .............................................................................................................. 22 
6.2 
Day 1 of Each Cycle (± 7 days) .......................................................................................................................... 24 
6.3 
Every 3 Cycles (Cycle 4, 7,10, ETC.,± 7 days) ............................................................................................... 24 
6.4 
Progression on Arm l ....................................................................................................................................... 25 
6.5 
End of Study (30 Days of Stopping Protocol Study Treatments) .............................................................. 25 
6.6 
Correlative/Special Studies ............................................................................................................................... 25 
7. 
THERAPEUTIC MODALITIES ..................................................................................................................... 29 
7.1 
Pharmacokinetics .................................................................................................................................................. 29 
7.2 
Dosage Selected, Preparation, and Schedule of Administration ................................................................ 33 
7.3 
Dose Modifications and Dose Delay ............................................................................................................... 37 
7.4 
Removing Patients from the Protocol ............................................................................................................ 43 
7.5 
Concomitant Medications and Supportive Care .......................................................................................... 43 
8. 
SAFETY EVALUATION AND REPORTING .................................................................................................... 44 
8.1 
Definitions ............................................................................................................................................................... 44 
8.2 
Recording and Grading ...................................................................................................................................... 44 
8.3 
Unexpected Adverse Events ............................................................................................................................. 45 
8.4 
Serious Adverse Events and Serious Adverse Drug Reactions ................................................................ 45 
8.5 
Reporting Serious Adverse Events 4 ................................................................................................................. 7 
8.6 
Safety Reports ...................................................................................................................................................... 48 
8. 7 
Unanticipated Problems ..................................................................................................................................... 48 
9. 
CRITERIA FOR OUTCOME ASSESSMENT /THERAPEUTIC RESPONSE .................................................... 49 
9.1 
Outcome Assessment ........................................................................................................................................... 49 
9.2 
Therapeutic Response ........................................................................................................................................ 49 
9.3 
Response Criteria for Control/Relieve/Eliminate Endpoints ................................................................... 51 
9.4 
Confirmatory Measures/Duration of Response .......................................................................................... 53 
10. 
DATA REPORTING AND REGULATORY REQUIREMENTS ........................................................................ 56 
10.1 Data Collection and Management .................................................................................................................... 56 
10.2 Study Monitoring and Quality Assurance ..................................................................................................... 57 
11. 
STATISTICAL CONSIDERATIONS .............................................................................................................. 58 
11.1 Endpoints ............................................................................................................................................................... 58 
11.2 Sample Size ........................................................................................................................................................... 59 
11.3 Toxicity Monitoring............................................................................................................................................. 59 


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11.4 Data Analysis ......................................................................................................................................................... 59 
12. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS ........................................................................ 60 
12.1 Roles and Responsibilitiies ................................................................................................................................. 60 
12.2 Ethical Considerations ......................................................................................................................................... 61 
12.3 Regulatory Documentation ................................................................................................................................. 61 
12.4 Protocol Amendments ......................................................................................................................................... 61 
12.5 Additional !RB Correspondence.......................................................................................................................... 63 
12.6 Written Informed Consent ................................................................................................................................ 64 
12.7 Protection of Privacy .......................................................................................................................................... 64 
12.8 Terminating of Modifying the Study .............................................................................................................. 65 
12.9 Noncompliance ....................................................................................................................................................... 65 
13. 
REFERENCES ................................................................................................................................................ 65 
APPENDIX A: PERFORMANCE STATUS CRITERIA ............................................................................................... 68 
APPENDIX B: MEDICATIONS WITH THE POTENTIAL FOR DRUG-DRUG INTERACTIONS ............................. 69 
APPENDIX C: LABORATORY MANUAL\CORRELATIVE STUDIES ....................................................................... 70 
APPENDIX D: SOP FOR ULTRASOUND\CT-GUIDED BIOPSY .............................................................................. 71 
APPENDIX E: LISTING OF EXPECTED/UNEXPECTED ADVERSE EVENTS ......................................................... 72 
APPENDIX F: GLOSSARY OF ABBREVIATIONS AND ACRONYMS ...................................................................... 75 
APPENDIX G. PILL DIARY ........................................................................................................................................ 79 
APPENDIX H: STANDARD OPERATING PROCEDURE FOR SHIPMENT OF CLINICAL SAMPLES .................... 80 
APPENDIX I: 1ST SAE REPORT ............................................................................................................................ 811 
APPENDIX J: PCCTC SERIOUS ADVERSE EVENT REPORT FORM ....................................................................... 82 
APPENDIX K: PCCTC BONESCAN ASSESSMENT TOOL ........................................................................................ 83 
APPENDIX L: HALABI NOMOGRAM (UPDATED ASCO 2013) ............................................................................... 84 


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1. 
INTRODUCTION, BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Every year in the United States 28,000 men die of metastatic prostate cancer.8 Since the 
introduction of hormonal therapy sixty years ago,9 progress in developing new treatments 
has been poor.10 The biological revolution of the past two decades has produced few useful 
targeted agents against prostate cancer. In 2012, metastatic prostate cancer remains a 
uniformly fatal disease. It is striking that while molecular subtyping has afforded 
therapeutic benefit and improved patient survival in other tumor types,11-14 no comparative 
advances have been gained in the context of prostate cancer. At present, all patients with 
metastatic prostate cancer are treated identically, and there are no means with which to 
select appropriate therapeutic regimens based on tumor profiling. 
The course of prostate cancer from diagnosis to death is best categorized as a series of 
clinical states (Figure 1). These clinical states involve the complex interplay of a network of 
signaling molecules that collectively promote net cell proliferation relative to cell death. 
Treatment options for patients with castrate resistant prostate cancer (CRPC) are limited 
and until recently only docetaxel was shown to improve survival. In the last year we had 4 
new agents; abiraterone acetate, cabazitaxel, enzalutamide and Sipuleucel-T approved for 
use in this clinical state. However the optimal sequencing of these agents is unknown. 
Moreover all patients with CRPC are treated identically and there is no means of identifying 
which patient population would benefit from a particular agent. 
Figure 1. Clinical states of prostate cancer 
1.2 Background 
This study is based on robust in vitro, in vivo, and clinical findings that have been reported. 
First, loss of retinoblastoma tumor suppressor (RB) function was recently identified as a 
major means by which castration-resistant tumors develop. Up to 60% of CRPC tumors 
examined to date show loss of RB function. Second. modeling this event in human xenografts 
demonstrated that loss of RB is sufficient to drive the transition to castration resistance. 
The underlying mechanisms by which RB loss promotes CRPC were illuminated, whereupon 
it was revealed that expression of the androgen receptor (AR) is under stringent RB control. 
Consonantly, loss of RB results in AR deregulation and bypass of androgen deprivation 
therapy, and investigation of human CRPC revealed that this occurrence is frequent in the 
clinical setting. Third, while RB-deficient tumors are resistant to androgen deprivation 
therapy, tumors lacking RB are compromised for DNA damage checkpoints that normally 
allow for repair after genomic insult. As a result, tumors devoid of RB function are 


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hypersensitive to treatment with agents that induce genotoxic stress. These collective 
findings strongly support the novel  hypothesis that leveraging RB status to tailor 
treatment for CRPC will improve outcomes for advanced disease. 
 Loss of RB function is a major effector of the transition to advanced prostate cancer: The RB 
tumor suppressor protects against tumor development in a large number of tissues; 
accordingly, RB function is ablated in early stages as a function of tumorigenesis in several 
human malignancies (e.g. breast, cervical and small cell lung cancer).15,16 
The function of RB in protecting against tumor development is manifest through the ability 
of this protein to act as a transcriptional repressor, binding to the regulatory region of genes 
whose functions are important for cell cycle progression and DNA replication. Recent 
interrogation of RB function in human prostate cancer does not fit this paradigm, and deep 
investigation illuminated five key features of RB action that have a significant impact on 
disease progression and therapeutic intervention: 
1.2.1 
 Knudsen and colleagues at Thomas Jefferson University observed in clinical specimens 
that RB expression (mRNA or protein) is retained in primary disease.1 
This premise was further validated by analyses of RB function and they have 
developed a unique mRNA "signature" using genetically modified tissues that 
accurately assesses RB function in any cell type.1,2 
Such analyses are critical, as tumors retaining RB expression can be devoid of RB 
function, as occurs through mutation of RB and or factors that induce excessive RB 
phosphorylation (thus suppressing RB tumor suppressor activity). They have 
further refined this gene signature (unpublished data), and recently developed a 
high density microarray chip that provides a robust measure of RB function built off 
of an FDA approved Affymetrix platform in accordance with GMP/GLP (Figure 2). 
For this proposal, RB status will be determined using immunohistochemistry but an 
accompanying, exploratory endpoint will be to assess clinically whether the RB chip 
can be used to assign RB functional status from tissue and circulating tumor cells. 
Figure 2. Development of the RB loss signature microarray chip. A refined version of the published RB loss-of- 
function gene expression signature was recently developed into a proprietary high density microarray chip 
(middle panel) that provides faithful measure of RB function. The right panel provides examples of data 
obtained from 3 samples that retain RB function vs. 3 from tumors wherein RB function has been suppressed. 


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1.2.2 
Using multiple methods to assess RB expression and activity, it was noted that RB loss 
of Junction is highly overrepresented in CRPC. 
A representative example of the data are shown in Figure 3 and in the study by 
Sharma et al. 1 
Using the combined analyses of RB expression and the RB signature, up to 60% of 
CRPCs show loss of RB activity. While the initial study examined over 150 CRPC 
specimens, enrichment of RB loss in the CRPC setting has been further confirmed by 
the work of Gerald and Sawyers,17 and in subsequent analyses of cohorts from Dr. 
Tapio Visakorpi (data not shown). Moreover, recent mouse models confirm the 
importance of RB in prostate cancer.18 
Figure 3. RB function is perturbed in the transition to CRPC. These data are taken from a recent comprehensive 
study (Sharma et al., J Clin Invest 2010) which assesses RB functional status in multiple tumor sets. As 
shown, the RB loss signature is highly overrepresented in CRPC (left). Quantification and statistical analyses 
(right) demonstrate that there is little evidence for loss of RB function in primary disease, whereas this event 
is frequent in CRPC. Based on this published (Sharma et al., 2010) and new preliminary data, analyses of over 
150 CRPCs demonstrate that RB loss of function occurs in up to 60% of CRPCs. 
1.2.3 
 Modeling of RB loss in multiple human xenografts unexpectedly revealed that ablation 
of RB function does not induce a significant tumor growth advantage prior to hormone 
therapy,1 thus indicating that in this tumor type, RB plays a role distinct from that in 
other tissues. 
Strikingly, in vivo castration challenge revealed that RB-deficient tumors are 
exquisitely resistant to castration therapy. A representative example of these data 
are shown in Figure 4 and in the article by Sharma et al. 1 
These observations were the first to suggest that in prostate cancer, RB serves a 
unique role to protect against the transition to lethal disease. 


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Figure 4. RB loss is sufficient to drive the transition to CRPC. Ablation of RB in human prostate cancer 
xenografts is sufficient to render castration resistance. An example is provided here, wherein isogenic pairs 
of human xenografts were examined +/- sh RNA directed against RB. RB ablation alone had no effect on 
tumor growth in the pre-castration setting (not shown but provided in1), whereas RB depletion strongly 
promoted castration-resistant growth (left) and a shorter time to biochemical failure serum PSA (right). 
1.2.4. 
 The underlying mechanisms of RB Junction were further explored, whereupon it was 
discovered that expression of the gene encoding the AR is under RB control. 
These data are extensive and not shown herein due to space limitations. Please see 
the recent study inf. Clin. Invest.,1and resulting commentary article inf Clin Invest.19 
In brief, loss of RB caused de-repression of the AR locus, excessive AR production, 
and castration-resistant (ligand independent) AR activity that proved sufficient to 
bypass hormone therapy. Thus, means to restore RB function would be of a 
significant therapeutic benefit. 
1.2.5. 
 Finally, RB status proved strongly predictive of surviva/,1as was confirmed using 
multiple cohorts. 
An example of these data is shown in Figure 5. 


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Figure 5. RB loss of function is associated with poor outcome. As was 
shown and described in detail the RB loss signature is associated with 
poor outcome, including a shorter time to recurrence free survival. 
Combined, these data identify RB tumor suppressor activity is critical to 
determine the outcome and possible treatments for patients with castrate 
resistant prostate cancer. 
1.2.6. 
Treatment of RB-deficient tumors: leveraging the loss of DNA damage checkpoints for 
clinical benefit 
Studies demonstrate that RB-deficient tumors acquire hyperactive AR activity and 
bypass first line hormone therapy. By contrast, it has been shown in multiple 
models of disease that RB-deficient cells lack cell cycle checkpoints that induce cell 
cycle arrest after genomic insult.1-3 
Thus, in model systems, RB-deficient tumor cells are hypersensitive to agents that 
induce genotoxic stress (including etoposide, radiation, and taxanes). Examples in 
fibroblasts and prostate cancer cells are shown in Figure 6. Furthermore, it was 
recently observed in breast cancer that patients harboring RB-deficient tumors 
showed improved survival upon treatment with chemotherapy.20 
Based on these findings, it is anticipated that stratification of patients with RB- 
deficient tumors into chemotherapy containing regimens will afford significant 
clinical benefit. 


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Figure 6. RB deficient tumors are hypersensitive to a subset of DNA damaging and chemotherapeutic agents. 
A. Early studies in fibroblasts revealed that RB-deficient cells are compromised for a subset of DNA 
damaging checkpoints and become hypersensitive to treatment with agents that induce genotoxic stress.21 
For example, fibroblasts deficient in RB are hypersensitive to cisplatin. Subsequent analyses revealed that 
the hypersensitization events are tissue specific. B. In vivo analyses show that RB deficient human prostate 
cancer cells are hypersensitive to ionizing radiation. C. Initial screening agents, wherein isogenic pairs of 
RB+ and RB- cells were treated with chemotherapeutics revealed that RB-deficient cells are also 
hypersensitive to microtubule poisons. These preliminary studies entailed only a brief exposure to low dose 
chemotherapy, so as to identify meaningful changes in survival that could be refined through multiple dosing. 
1.3 
Rationale 
The clinical dilemma that faces physicians once a patient relapses from primary hormonal 
therapy is whether to initiate secondary endocrine therapies such as anti- 
androgens/androgen biosynthesis inhibitors or move directly to chemotherapy. Currently, 
there are no biomarkers to help us identify patients that may still be androgen receptor 
sensitive and many clinicians will use a trial and error approach to patients thus delaying 
patients from receiving chemotherapy in a timely manner. Methods to distinguish androgen 
receptor sensitive vs. insensitive patients would greatly personalize the approach of CRPC 
and is an unmet clinical need. 
Recently, the drug abiraterone acetate, a 17 lyase inhibitor, has shown to improve the 
survival of CRPC patients that have failed docetaxel based chemotherapy.4 While 
abiraterone acetate has recently received FDA approval for CRPC that have failed prior 
docetaxel chemotherapy, more recently abiraterone acetate has shown clinical benefit in 
the pre-chemotherapy setting (RB+ and RB- tumors). Abiraterone acetate improved 
radiographic progression-free survival (16.5 vs. 8.3 months, hazard ratio 0.53, p<0.001) 
showed a trend toward improved overall survival, and significantly delayed initiation of 
chemotherapy in patients with metastatic castration-resistant prostate cancer. Based on the 
cumulative data on abiraterone acetate, the FDA has approved the use in pre-chemotherapy 
setting.s 
Abiraterone acetate is a safe drug and the most common side effects of the medication 
appear to be hypertension, hypokalemia and fluid retention which are likely from excess 
mineralocorticoid secretion, which are mostly corrected with the concomitant use of 
prednisone. Most other adverse events (AEs) were Grade 1 or 2 toxicities in prior studies. 
Due to the ease of administration, the recent results showing clinical benefit in CRPC prior 
to chemotherapy along with its favorable safety profile, it is expected that abiraterone 
acetate will be used extensively prior to chemotherapy. However, there is still a substantial 


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proportion of patients that do not clinically respond to abiraterone acetate treatment and 
pre-clinical studies suggest that these tumors may have a RB deficient phenotype as 
described above. Thus, these patients may benefit from earlier chemotherapy. 
Docetaxel is the standard chemotherapy in the first line setting for CRPC.22 Cabazitaxel is a 
more potent micro-tubule inhibitor that has improved overall survival in CRPC patients that 
have failed docetaxel chemotherapy when compared to mitoxantrone.6 Cabazitaxel's most 
common side effects are hematological with the dose limiting side effect being neutropenia. 
Other Grade 3 toxicities noted were diarrhea, fatigue, asthenia and back pain. Febrile 
neutropenia was observed in 8% of patients in the second line setting. A head to head 
comparison of docetaxel and cabazitaxel is ongoing; but it is generally considered that 
cabazitaxel will be equivalent or better than docetaxel in the first line setting. Therefore, it 
would be reasonable to consider a combination of abiraterone acetate and cabazitaxel in 
this setting given the non- overlapping toxicities. There is a phase I\II trial of cabazitaxel 
and abiraterone acetate in patients that have progressed after treatment with docetaxel 
(Sanofi sponsored study, NCT01511536). This study has completed dose escalation part of 
the study where 2 dose levels of cabazitaxel, 20 and 25 mg/m2 IV every 3 weeks, were 
administered with abiraterone acetate 1000 mg daily and prednisone 5 mg po BID. The 
maximal tolerated dose was established at cabazitaxel 25 mg/m2 dose level without dose 
limiting toxicities in 6 evaluable patients (personal communication Massard et al.; abstract 
submitted ASCO 2013). 
This is an exploratory randomized phase II trial of abiraterone acetate\prednisone (AA) 
alone followed by cabazitaxel on progression of disease versus the combination of 
abiraterone acetate and cabazitaxel (AA+C) upfront in patients with chemotherapy nai've 
CRPC. Since little is known about the RB status in patients treated on prior trials with 
abiraterone acetate or chemotherapy, the RB status of all patients will be determined prior 
to treatment at study entry to help develop a possible marker that may help select 
treatment in the future. In this study, the RB status will not be used to determine treatment 
but to determine the feasibility in assessing the RB status in patients and to predict the 
prevalence of the RB positive and negative tumors in patients treated with abiraterone 
acetate\prednisone or abiraterone acetate\prednisone + cabazitaxel. This will allow us to 
understand the effects of treatment in these populations and in the future could identify 
patients that may benefit from chemotherapy earlier. While, this technology for RB profiling 
has shown robust results in the laboratory, this will be the first trial to determine RB 
profiles prospectively in patients and data from this trail will help guide future randomized 
trials that can be designed to evaluate the utility of RB status in patients with CRPC. 
In summary, this study is a non-comparative randomized trial to 1) extend the pre-clinical 
work on RB status in prostate cancer to patients, 2) explore the feasibility of determine RB 
status in patients tumors and circulating tumor cells, 3) to determine the prevalence of RB 
status in prostate tumors that are chemotherapy nai've, 4) to determine the safety and 
clinical outcomes in chemotherapy nai've prostate cancer with the combination of AA + C, 
and 5) correlate the clinical outcomes based on RB status and treatment in patients. The 
information derived from this study is critical for the development of RB as biomarker and 
designing\powering future studies that will help select those patients that will need 
chemotherapy in their disease course. 


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2. 
OBJECTIVES 
2.1 
Primary Objective 
1. To determine the radiographic progression free survival (rPFS) of abiraterone 
acetate\prednisone with and without cabazitaxel in patients with chemotherapy naive 
CRPC. 
2.2 
Secondary Objectives 
1. To determine PSA progression free survival (PSA PFS) in patients treated with 
abiraterone acetate\prednisone with and without cabazitaxel in patients with 
chemotherapy naive CRPC 
2. To determine the proportion of chemotherapy naive CRPC patients with measurable 
disease regression based on RECIST treated with abiraterone acetate with and without 
cabazitaxel. 
3. To determine the overall toxicity and survival of abiraterone acetate with and without 
cabazitaxel in patients with chemotherapy naive CRPC. 
4. To determine the proportion of patients that have an objective response by RECIST and 
post-therapy PSA decline using a waterfall plot in patients that are treated cabazitaxel 
after progression on the abiraterone\prednisone alone arm 
2.3 
Correlative Studies 
1. To prospectively estimate the proportion of patients that have tumors that are RB 
negative\positive based on immunohistochemistry and RB gene signature from the 
baseline tumor biopsy samples. 
2. To determine the feasibility of obtaining the RB status for prostate cancer on circulating 
tumor cells at baseline. 
3. 
PATIENT SELECTION 
3.1 
Inclusion Criteria 
Patient needs to have a histologic or cytologic diagnosis of prostate cancer 
3.1.1 
Documented progressive metastatic CRPC based on  at least one of the following 
criteria: 
a) PSA progression defined as 25% increase over baseline value with an increase 
in the absolute value of at least 2 ng/mL that is confirmed by another PSA level 
with a minimum of a 1 week interval and a minimum PSA of 2 ng/mL. 
b) Soft-tissue progression defined as an increase 20% in the sum of the LD of all 
target lesions based on the smallest sum LD since treatment started or the 
appearance of one or more new lesions. 
c)  Progression of bone disease (evaluable disease) or (new bone lesion(s)) by bone 
scan. 
3.1.2 
Agree to undergo a biopsy of at least one metastatic site or primary prostate for 
determination of the RB status. Adequate archival metastatic tissue can be used if 


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available in lieu of a biopsy if done when patient had CRPC (within 6 months of 
treatment start). 
3.1.3 
ECOG performance status of0-2. 
3.1.4 
Age 18years. 
3.1.5 
Have testosterone 
< 50 ng/dL. Patients must continue primary androgen 
deprivation with an LHRH/GnRH analogue (agonist or antagonist) if they have not 
undergone orchiectomy. 
3.1.6 
Patients on long term (>6 months) anti-androgen therapy (e.g. flutamide, 
bicalutamide, nilutamide) will need to be off anti-androgen for 4 weeks (wash out 
period) and show evidence of disease progression off the anti-androgen. Patients 
that have been on an anti-androgen 6 months or less will need to discontinue anti- 
androgen therapy prior to treatment start (no wash out period required). 
3.1.7 
 Patients must have adequate organ and marrow function as defined below obtained 
within 14 days prior to treatment start: 
 
ANC 
Hemoglobin 
Platelet count 
Creatinine 
Potassium 
Bilirubin 
SGOT (AST) 
SGPT (ALT) 
1,500/µl 
9g/dL 
100,000/µl 
s; 1.5 x the institutional upper limit of normal (ULN) 
within institutional range 
s; ULN (unless documented Gilbert's disease) 
:-::; 2.5 x ULN 
 
:-::; 2.5 xULN 
 


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3.1.8 
The effects of cabazitaxel and abiraterone acetate on the developing human fetus at 
the recommended therapeutic dose are unknown. Men must agree to use adequate 
contraception prior to study entry, for the duration of study participation and for at 
least 3 months thereafter. 
3.1.9 
 Patients must be able to take oral medication without crushing, dissolving or 
chewing tablets. 
3.1.10  Patients may have received prior radiation therapy or major surgery. However, at 
least 21 days prior to treatment start must have elapsed since completion of 
radiation therapy or major surgery and patient must have recovered from all side 
effects at the time of randomization. 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document that is approved by the local institutional review board. 
3.2 
Exclusion Criteria 
3.2.1 
 Patients may not be rece1vmg any other investigational agents. Any prior 
investigational therapeutic products must be stopped at least 28 days (4 week 
washout) prior to treatment start. 
3.2.2 
No prior exposure to abiraterone acetate or other specific CYP-17 inhibitors. 
3.2.3 
 No prior chemotherapy regimen. Prior isotope therapy with Strontium-89, 
Samarium or RAD223 should be completed at least three months (12 weeks) prior 
to treatment start. 
3.2.4 
No ;:: grade 2 peripheral neuropathy 
3.2.5 
 Patients who have had antifungal agents (itraconazole, fluconazole) within 4 weeks 
prior to treatment start or those who have not recovered from AEs due to these 
agents administered more than 4 weeks earlier. 
3.2.6 
 Patients with a history of pituitary or adrenal dysfunction, active or symptomatic 
viral hepatitis or chronic liver disease are not eligible. 
3.2.7 
 Patients with known symptomatic brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other AEs. 
3.2.8 
 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to cabazitaxel or other drugs formulated with polysorbate 80; or 
abiraterone acetate. 
3.2.9 
 Patients may continue on a daily Multi-Vitamin, calcium and Vitamin D, but all other 
herbal, alternative and food supplements (i.e. PC-Spes, Saw Palmetto, St John Wort, 
etc.) must be discontinued before treatment start. Patients must not be planning to 
receive any concurrent cytotoxic chemotherapy, surgery for their prostate cancer, or 
radiation therapy during protocol treatment. 


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3.2.10  Patients on stable doses of bisphosphonates or the RANK-L inhibitor, Denosumab, 
which have been started no less than 4 weeks prior to treatment start, may continue 
on 
this 
medication, 
however 
patients 
are 
not 
allowed 
to 
initiate 
bisphosphonate/Denosumab therapy during the study. 
3.2.11  Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure (New York Heart Association Class 
III and IV heart failure), unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that, in the opinion of the investigator, would limit 
compliance with study requirements or concurrent medications that alter cardiac 
conduction. 
3.2.12  Patients with a "currently active" second malignancy other than non-melanoma skin 
or superficial urothelial cancers are not eligible. Patients are not considered to have 
a "currently active" malignancy if they have completed therapy and are now 
considered without evidence of disease for 2 years. 
3.3 
Prohibited Concomitant Medications 
• 
Chemotherapy 
• 
Immunotherapy 
• 
Radiopharmaceuticals like Strontium or Samarium or Radium-223 
• 
S alpha reductase inhibitors 
• 
Spironolactone 
• 
Diethy-Stilbestrol 
• 
Ketoconazole 
• 
Newer medications targeting androgen receptors. 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, 
over-the-counter medications, or alternative therapies must be documented on the case 
report form (CRF). The principal investigator should be alerted if the patient is taking any 
agent which interacts with CYP450 system as found in Appendix B (a listing of medications 
with the potential for drug-drug interactions). 
4. 
ENROLLMENT PLAN AND SUBJECT REGISTRATION 
4.1 
Enrollment Plan 
4.1.1 
Participating Study Centers 
This study is anticipated to be conducted in S site(s). 
4.1.2 
Recruitment 
Potential research subjects will be identified by a member of the patient's treatment team, 
the protocol investigator, or research team at participating centers from Medical Oncology, 
Radiation Oncology and Urology offices. Investigators will screen the patient's medical 
records for suitable research study subjects and discuss the study and their potential for 
enrolling in the research study. 


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4.2 
Registration Procedure 
After eligibility screening and confirmation that a patient is eligible, patients who are 
selected to participate will be registered with the PCCTC Caisis EDC, the PCCTC's Clinical 
Data Management System (CDMS). A record of patients who fail to meet eligibility criteria 
(i.e., screen failures) will be maintained. Patient registration must be complete before 
beginning any treatment or study activities. A complete, signed study consent and HIPAA 
authorization are required for registration. 
4.2.1 
Registration 
• 
Confirm eligibility as defined in Section 3 Patient Selection. 
• 
Obtain informed consent, by following procedures in Section 12.6 Written 
Informed Consent. 
• 
Obtain completed or partially completed protocol specific Eligibility 
Checklist. 
• 
All participants will be registered through PCCTC Caisis EDC, the PCCTC's 
CDMS. 
Central registration for this study will take place at MSKCC. To complete registration 
and enroll a participant, the study staff at that site must contact the designated 
research staff at the PCCTC to notify him/her of the participant registration. The site 
staff then needs to email registration/ eligibility checklist and source documents to 
the PCCTC at PCCTC@mskcc.org.  (Note: Source documentation of eligibility is 
not required for MSKCC participants.) 
These documents must be sent for each enrollment within 24 hours of the 
informed consent form being signed. 
Upon receipt, the research staff at the PCCTC will conduct an interim review of all 
documents for all non-MSKCC participants. If the eligibility checklist is not 
complete or source documentation is missing, the patient will be registered pending 
enrollment and the site is responsible for sending the completed registration 
documents within 30 days of the consent. 
If the external registration submission is complete, the participating site IRB has 
granted approval for the protocol, and the site has been activated by MSKCC, the 
PCCTC will register the participant non-MSKCC participants. MSKCC participants 
will be fully registered by MSKCC. 
Once the participant is registered, the participant will be assigned a PCCTC Caisis 
Subject ID. This number is unique to the participant and must be written on all data 
and correspondence for the participant. This PCCTC Caisis Subject ID will be 
relayed back to study staff at the registering site via e-mail and will serve as the 
enrollment confirmation. This number is unique to the participant and must be 
written on all data and correspondence for the participant. 
Participating sites will register subjects locally per their Institutional guidelines and 
the PCCTC will register all non-MSKCC participants with MSKCC's Protocol 


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Participant Registration (PPR) Office per MSKCC's guidelines. MSKCC participants 
will be fully registered by MSKCC with PPR. 
4.2.2 
Institutional Registration 
Patient registration at each study site/institution will be conducted according to the 
institution's established policies. Patients must be registered with the PCCTC, 
MSKCC and their local site/institution before beginning any treatment or study 
activities. 
At MSKCC, all participants must be pended with MSKCC's Protocol Participant 
Registration (PPR) Office prior to submitting registrations to the PCCTC. 
The PCCTC will register all non-MSKCC participants with MSKCC's Protocol 
Participant Registration (PPR) Office per MSKCC's guidelines. 
MSKCC will register all MSKCC participants with MSKCC's Protocol Participant 
Registration Office (PPR) per MSKCC's guidelines. 
5. 
RANDOMIZATION 
This is a randomized phase II trial in which 80 patients will be randomized with equal 
probability to one of two possible treatment regimens: abiraterone acetate\prednisone 
(AA) or AA plus cabazitaxel (AA+C). The randomization will be stratified by Halabi 
nomogram (Appendix L) based on low (defined as ( 166.6 points in the nomogram) or high 
risk(>166.6 total points)7. Patients will be randomized after the investigator has verified 
that all eligibility criteria have been met and the patient is registered to the study. Patients 
will be randomized to receive abiraterone acetate\prednisone (AA) (Arm 1) or AA plus 
cabazitaxel (AA+C) (Arm 2) in a 1:1 ratio. 
Accrual is expected to be completed within 2 years after trial activation at participating 
sites. 


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- 
- 
- 
6. 
STUDY ASSESSMENTS BY VISITS 
• Informed consent and research 
I 
 
 
 
 
 
 
Dayl 
 
 
 
 
 
 
Dayl 
 
 
 
 
 
 
Dayl 
 
 
 
 
 
and etc  - 
CT\MRI of the chest or CXR, 
abdomen and pelvis, and 
X 
X 
X 
radionuclide bone scanc 
I Tumor Measurementc 
X 
X 
X 
CBC, differential, Platelets0 
Serum Chemistry (see Lab/ 
Correlatives Studies Manual) 
Liver Function Tests E 
PSA 
Serum Testosterone 
Serum Triglycerides 
X 
X 
X 
X 
X 
X 
X 
XE 
XE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XE 
XE 
X 
X 
X 
X 
X 
X 
Tumor BiopsyF 
X 
XH 
Circulating Tumor Cells by EPICG 
X 
X 
X 
Androgen PanelM 
X 
X 
X 
 Arm1 
 
Abiraterone acetate 1000 mg po 
daily+ prednisone 5 mg po BID 
Screening 
Within 28 days 
Within 14 days 
of treatment 
of treatment 
start 
start 
One Cycle= 3 Weeks (21 days)A 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 
4, 7, 10 
EQSK I 
 
 
authorization/ HIPAA form 
X 
Demographics, medical history, 
histologic and radiologic 
confirmation of disease 
X 
Physical examination, vitals, 
weight, blood pressure8 
X 
X 
X 
X 
X 
X 
Height 
X 
Karnofsky or ECOG performance 
status 
X 
X 
X 
X 
X 
X 
Halabi Nomogram Risk 
X 
EKG 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Toxicity/Adverse Event 
assessments 
X 
X 
X 
X 
X 


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, 
- 
X 
- 
, 
X 
I Plasma for cDNA 
I 
X 
X 
X 
Abiraterone/Prednisone 
CabazitaxelI 
Arm 2: 
Cabazitaxel 25 mg/m2 IV every 3 
Screening 
One Cycle= 3 Weeks (21 days)A 
weeks + abiraterone acetate 1000 
mg po daily + prednisone 5 mg 
Within 28 days 
of treatment 
Within 14 days 
of treatment 
Cycle 1 
Cycle 2 
Cycle 
Cycle 
10, 13, 
EOSK 
po BID 
start 
start 
Dayl 
Day 1 
3-9 
and etc - 
Informed consent and research 
X 
authorization/ HIPAA form 
Demographics, medical history, 
histologic and radiologic 
X 
confirmation of disease 
Physical examination, vitals, 
weight, blood pressure8 
Height 
Karnofsky or ECOG performance 
status 
Halabi Nomogram Risk 
EKG 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
Concomitant medications 
X 
Toxicity/Adverse Event 
assessments 
X 
X 
X 
X 
X 
X 
X -
X 
CT\MRI of the chest or CXR, 
abdomen and pelvis, and 
X 
radionuclide bone scanc 
C4,C7 
X 
X 
I Tumor Measurementc 
X 
CBC, differential, Platelets0 
Serum Chemistry (see Lab / 
Correlative Studies Manual) 
Liver Function Tests E 
PSA 
Serum Testosterone 
Serum Triglycerides 
 
 
 
xo 
X 
X 
X 
X 
XE 
X 
X 
X 
X 
C4,C7 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
XE 
XE 
X 
X 
X 
X 
X 
X 
X 
C4,C7 
X 
X' 
X ---------------------------------- X 
r 
! 


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Page 21 
 
 
 
b 
 0
 
p 
s 
y 
Arm 1: 
Abiraterone\Prednisone 
- 
- 
A: All visits have a window of± 7 days 
B: Patients are to be encouraged to measure blood pressure weekly. 
C: CT scans/MRI (to follow measurable disease) and bone scans (to follow bone disease) are required every 3 cycles beginning on Cycle 4 until evidence of 
progression or relapse. Patients who have received a chest CT (or MRI) need not have a chest x-ray. Scans may be done up to ±7 days prior to beginning a 
cycle. Confirmatory scans should also be obtained at least 4 weeks following documentation of objective response. End of Study scans can be performed± 
30 days from End of Study Visit 
D: During the first cycle of cabazitaxel therapy, CBC will be obtained weekly. CBC: White blood cells count (WBC), red blood cell count (RBC), hemoglobin 
(HGB), hematocrit (HCT),, platelet count (UNVPLT), neutrophils (NEUTP), lymphocytes (LYMP). 
E: Additional liver function tests (aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin (TBILI)) measured every 2 weeks for the first 
4 cycles of treatment. These labs may be done locally. 
F: Adequate archival metastatic tissue can be used lieu of the baseline biopsy if done when patient had CRPC (within 6 months of treatment start). 
G: Will be performed at baseline, Cycle 2, and End of Study. 
H: A second optional tumor biopsy will be requested in patients with confirmed radiographic progression of disease on abiraterone acetate\prednisone 
alone arm. Biopsy will take place prior to starting cabazitaxel 
I: For Arm 1: On confirmed radiographic progression of disease, the abiraterone acetate will be discontinued and patients will be treated with cabazitaxel 
25mg/m2 IV every 3 weeks for a maximum of 9 cycles at the discretion of the treating physician. CT scans/MRI and bone scans are required every 3 cycles 
of cabazitaxel treatment beginning on Cycle 4. End of Study scans can be performed ± 30 days from End of Study Visit. Patients will continue to have 
procedures performed as outline in section 6.2 and 6.3. Please see section 6.4 for additional Progression on Arm 1 details. 
J: For Arm 2: Patients will get a maximum of 9 cycles of cabazitaxel and if the patients have not shown evidence of confirmed radiographic progression 
after 9 cycles of cabazitaxel, patients will continue on the abiraterone acetate and prednisone until disease progression or until the therapy is not 
tolerated. Patients will continue to have procedures perform as outline in section 6.2 and 6.3 
K: End of study visit must occur within 30 days of stopping study treatments. Patients withdrawn from the study because of AEs will be followed until the 
AE has either resolved or stabilized (minimum of every 4 weeks). 
L: Study treatments must occur within 7 days of randomization 
M: Testosterone, androstenedione, DHEAS 
Treatment/Intervention/Dose-modification schema 
Figure 7. Treatment schema 
All patients will have a tumor biopsy performed on an assessable metastatic tumor or 
primary prostate. Adequate archival metastatic tissue can be used lieu of the baseline 
biopsy if done when patient had CRPC (within 6 months of treatment start). RB status will 
 
 
 
 p
 D
 b
 
 0
 p s
 y
 
Arm2: 
Cabazitaxel + 
Abiraterone\Prednisone 
Cabazitaxel 
 
 
Tumor BiopsyF 
X 
Circulating Tumor Cells by EPICG 
X 
X 
X 
Androgen Panel 
X 
X 
X 
Plasma for cDNA 
X 
X 
X 
 
Abiraterone /Prednisonel 
X ------------------------------------- Xl 
Cabazitaxell 
X ------------------------- X 


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be determined by the IHC stains (RB positive or negative) at Thomas Jefferson University. 
All patients will also have circulating tumors cells collected as part of the correlative 
studies. 
1. Arm 1: Abiraterone acetate 1000 mg po daily + prednisone 5 mg po BID 
On confirmed radiographic progression of disease the abiraterone acetate will be 
discontinued and patient will be treated with cabazitaxel 25 mg/m2 IV every three weeks 
for a maximum of 9 cycles at the discretion of the treating physician. A second tumor biopsy 
may be performed prior to starting cabazitaxel. Premedications should be given as per 
outlined below. 
2. Arm 2: CabazitaxeI 25 mg/m2 IV+ abiraterone acetate 1000 mg po daily+ prednisone 
5 mgpo BID 
Patient will get a maximum of 9 cycles of cabazitaxel and if the patients have not shown 
evidence of confirmed radiographic progression after 9 cycles of cabazitaxel, patients will 
continue on the abiraterone acetate and prednisone until disease progression or until the 
therapy is not tolerated. 
Abiraterone acetate 1000 mg po daily+ prednisone 5 mg po BID. No food should be consumed 
for at least two hours before the dose of abiraterone acetate is taken and for at least one hour 
after the dose of abiraterone acetate is taken. 
IV cabazitaxel 25 mg/m2 IV every 3 weeks with premedications according to institutional 
standards 
The use of G-CSF support is allowed after cycle 1 of therapy at the investigators discretion 
according to the ASCO guidelines. G-CSF may be administered to reduce the risks of 
neutropenia complications associated with cabazitaxel use. Primary prophylaxis with G-CSF 
should be considered in patients with high-risk clinical features (age > 65 years, poor 
performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, 
poor nutritional status, or other serious co-morbidities) that predispose them to increased 
complications from prolonged neutropenia. Therapeutic use of G-CSF and secondary 
prophylaxis should be considered in all patients considered to be at increased risk for 
neutropenia complications. 
6.1 
Screening/Pretreatment Assessment 
Before initiating any screening activities, the scope of the study should be explained to each 
patient. Patients should be advised of any known risks inherent in the planned procedures, 
any alternative treatment options, their right to withdraw from the study at any time for 
any reason, and their right to privacy. After this explanation, patients should be asked to 
sign and date a Notice of Privacy Practice research authorization/HIPAA form and an IRB- 
approved statement of informed consent that meets the requirements of the Code of 
Federal Regulations (Federal Register Vol. 46, No. 17, January 27, 1981, part 50). 
The screening visit will determine patient eligibility according to the inclusion and 
exclusion criteria (Sections 3.1 and 3.2). Patients will complete screening/baseline 


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assessments prior to treatment start. The following assessments will be performed at this 
visit. 
Within 28 days prior to treatment start: 
• 
Informed consent and research authorization/ HIPAA form 
• 
Demographics, medical history, histologic and radiologic confirmation of disease 
• 
Discuss concurrent medications (see Appendix B for a listing of medications with the 
potential for drug interactions) 
• 
Correlative studies: 
o 
Tumor biopsy (Note: Adequate archival metastatic tissue can be used in lieu of 
the baseline biopsy if done when the patient had CRPC, within 6 months of 
treatment start) 
• 
Imaging (If imaging is being used to document progression of disease for study 
eligibility, assessments must be performed within 28 days prior to treatment start. Any 
other assessments not utilized for documentation of disease progression but are 
required for study entry can be performed within 42 days prior to treatment start) 
o 
 Contrast-enhanced CT of the chest and contrast-enhanced CT of the abdomen 
and pelvis. For patients unable to receive contrast-enhanced CT of the chest 
abdomen and pelvis, a chest X-ray and MRI of the abdomen and pelvis will be 
allowed. 
o 
Radionuclide bone scan 
Within 14 days prior to treatment start: 
• 
Physical exam including vital signs, weight, height and EKG 
• 
Karnofsky or ECOG performance status (Appendix A) 
• 
Halabi Nomogram Risk (Appendix L) 
• 
Laboratory studies 
o 
CBC 
o Serum Chemistry 
o Liver Function Tests 
o 
PSA 
o Serum Testosterone 
o Serum Triglycerides 
• 
Correlative studies 
o Circulating Tumor Cells by EPIC 
o Androgen Panel 
o 
Plasma for cDNA 
Relevant information should be documented. The institutional registration should be 
finalized, and appropriate documents (i.e., signed informed consent, research 
authorization/HIPAA form, eligibility checklist, and supporting source documentation for 
eligibility questions) emailed to the PCCTC. Information for patients who do not meet the 
eligibility criteria to participate in this study (i.e., screening failures) should be captured in 
Caisis at the pretreatment assessment. 


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6.2 
Day 1 of Each Cycle(± 7 days) 
On each visit, the following assessments will be performed: 
• 
Physical examination, vitals, weight, blood pressure 
• 
Karnofsky or ECOG performance status (Appendix A) 
• 
Discuss concurrent medications 
• 
Toxicity/ Adverse Event assessments 
• 
CBC (additional weekly CBCs drawn during first cycle of cabazitaxel treatment) 
• 
Serum Chemistry 
• 
 Liver Function Tests (Additional liver function: aspartate transaminase (AST), alanine 
transaminase (ALT), total bilirubin (TBILI) measured every 2 weeks for the first 4 cycles 
of treatment. These labs may be done locally) 
• 
PSA 
• 
Circulating Tumor Cells by EPIC, Androgen Panel, cDNA (Cycle 2 only) 
Note: 
Arm 1 patients are required to receive the above assessments for Cycles 1-3 and every 3 
cycles± 7 days starting from Cycle 4 (Cycle 4, 7, 10, etc.). On confirmed radiographic 
progression of disease on abiraterone acetate, the patients will receive the assessments 
listed in section 6.2 on Day 1 of each cycle of cabazitaxel and will follow the Arm 2 
treatment schedule from C1D1 including imaging. 
Arm 2 patients are required to receive the above assessments for Cycles 1-9. Patients 
continuing abiraterone acetate after completing 9 cycles of cabazitaxel will receive the 
above assessments every 3 cycles starting with Cycle 10 (Cycle 13, 16, 19, etc.) 
6.3 
Every 3 Cycles (Cycle 4, 7,10, ETC.,± 7 days) 
• 
Imaging 
o  Contrast-enhanced CT of the chest and contrast-enhanced CT of the abdomen 
and pelvis. For patients unable to receive contrast-enhanced CT of the chest 
abdomen and pelvis, a chest X-ray and MRI of the abdomen and pelvis will be 
allowed. 
o Radionuclide bone scan 
• 
Tumor Measurement 
• 
Serum Triglycerides 
6.4 
Progression on Arm 1 
On confirmed radiographic progression of disease, the abiraterone acetate will be 
discontinued. 
Cabazitaxel treatment must be initiated within  28 days of discontinuing abiraterone 
acetate. 
Patients will have a new baseline CTC, cDNA, and androgen panel drawn within 14 days of 
starting therapy with cabazitaxel. 


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6.5 
End of Study (30 days of stopping protocol study treatments) 
A patient may be discontinued from study treatment at any time if the patient or the 
Investigator feels that it is not in the patient's best interest to continue on study. The 
following is a list of possible reasons for early discontinuation of study treatment 
• 
Disease progression per protocol 
• 
Patient is not compliant with study procedures 
• 
Lost to follow-up 
• 
Patient withdrawal of consent 
• 
Treatment-limiting adverse event 
A treatment-limiting adverse event is any AE related to protocol therapy experienced 
during the study resulting in treatment termination. Patients withdrawn from the study 
because of AEs will be followed until the AE has either resolved or stabilized (minimum of 
every 4 weeks). Reasons for premature withdrawal should be determined and noted. 
The following study activities will occur at End of Study Visit: 
• 
Physical exam including vital signs, weight, blood pressure 
• 
Karnofsky or ECOG performance status (Appendix A) 
• 
Discuss concurrent medications 
• 
Toxicity/ Adverse Event assessments 
• 
Imaging (Can be performed± 30 days from End of Study Visit) 
o  Contrast-enhanced CT of the chest and contrast-enhanced CT of the abdomen 
and pelvis. For patients unable to receive contrast-enhanced CT of the chest 
abdomen and pelvis, a chest X-ray and MRI of the abdomen and pelvis will be 
allowed. Radionuclide bone scan 
• Tumor Measurement 
• CBC 
• Serum chemistry 
• Liver Function Tests 
• PSA 
• Serum Testosterone 
• Circulating Tumor Cells 
• Androgen Panel 
• Plasma for cDNA 
6.6 
Correlative/Special Studies 
Each patient will have the following specimens obtained at the study site as described 
below: 
a)  A paraffin embedded tumor sample (block or 5-10 unstained slides; S micron 
thickness) from a new biopsy of a metastatic site of disease or prostate primary 
within 4 weeks prior to treatment start. Adequate archival metastatic tissue can be 
used lieu of the baseline biopsy if done when patient had CRPC (within 6 months of 
treatment start). 


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b)  In a patient undergoing a soft tissue biopsy to determine RB status, an additional 
tumor sample will be collected to be placed in media/serum for explant culture in 
sites participating in the explant protocol. 
c)  Blood for circulating tumor cells by EPIC: screening (baseline), Cycle 2, and End of 
Study - total of 3 tubes (1 Streck and 2 PAXgene) 
d) Blood for androgen panel by HPLC (pre-treatment and End of Study, 1 red top tube). 
e) Plasma collected for circulating DNA ( pre-treatment and End of Study, Streck™ Cell- 
Free DNA BCT tube (Streck Inc.) 
The rationale, and a brief overview, for collection and handling of these specimens are 
described below. Further technical details regarding biopsies of metastatic sites, handling 
and shipping of these biopsy specimens can be found in the Lab/Correlative Studies Manual. 
6.6.1. 
Collection and Handling of Biopsy Specimens 
Patients will be scheduled for a CT or ultrasound-guided biopsy of a bone or soft 
tissue abnormality consistent with prostate metastasis or transrectal ultrasound 
guided biopsy of a recurrent tumor in the prostate. PET or MRI guided biopsies are 
acceptable. Alternatively, a standard bone marrow biopsy of the posterior iliac bone 
may be obtained. The site of biopsy will be determined after review of available 
radiographs, CT, MRI, ultrasound and/or bone scan, and will be selected based 
whatever site is expected to result in the best access, best yield and is safe for the 
patient. Verbal and written informed consent will be obtained per institutional 
standards. While the exact number of specimens obtained depends on the size of the 
target, the difficulty of the procedure, and risk of complications, the goal is to obtain 
2-3 samples. 
The soft or bone tissue samples will be sent to pathology for analysis to confirm the 
diagnosis of prostate cancer (at the Institution of participant registration). A portion 
of the confirmed paraffin tumor embedded block will be sent to Thomas Jefferson 
University for RB analysis as described below in Section 6.6.5. Shipping of specimens 
after collection. 
If patient undergoes a soft tissue biopsy to determine RB status, an additional tumor 
sample will be collected in media/serum for explant culturing in sites participating 
in the explant protocol. 
All tissue samples will be labeled with the clinical protocol number, the patient's 
study registration number, and specimen ID. In addition, a separate information 
sheet accompanying each specimen will be filled out (Please see Lab/Correlative 
Studies Manual). 
Following biopsy, samples from metastatic sites or recurrent disease in the prostate 
need to be shipped to Thomas Jefferson University per shipping directions 
described below. Samples may be shipped Monday through Thursday. Samples will 
not be accepted on the weekends. 
6.6.2. 
Circulating tumor cells (CTC): sample collection procedure 
Blood will be collected at screening (baseline), Cycle 2, every 3 cycles beginning on 
Cycle 4 and End of Study. At each of these time point, blood samples will be drawn 


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Cabazitaxel and Abiraterone Acetate 
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into one 10-mL evacuated blood draw tubes (Cell-Free DNA BCT Streck tube; EPIC) 
and two 2.5 ml PAXgene tubes. These blood samples can be maintained at room 
temperature. The Streck tube will be shipped to EPIC SCIENCES for overnight 
delivery. The PAXgene tubes can be shipped overnight at ambient temperatures or 
frozen and batch shipped to Memorial Sloan Kettering Cancer Center. See the study- 
specific laboratory manual for further details on CTC sample collection, processing 
and shipping (Laboratory/Correlatives Studies Manual). These samples will be used 
to give cell count of CTC and the tumor cells and the DNA\RNA will be isolated to 
perform genomic analysis for RB function. 
6.6.3. 
Procedures for processing tumor samples, plasma and serum samples 
 RB IHC from paraffin blocks 
Formalin-fixed paraffin-embedded tissue from 400 archived specimens with 
prostate cancer will be placed in a tissue microarray (TMA) using the Veridiam ® 
tissue arrayer with Institutional IRB approval. 40 cancer cases will be placed in a 
single TMA block with control cases. Immunohistochemical (IHC) staining with the 
RB monoclonal antibody from Cell Signaling Technology ® will be applied [RB 
(4H1) Mouse mAb #9309L]. An automated IHC staining protocol (ultra View DAB 
vl.02.0018) will be used on the Ventana automated stainer (Benchmark XT, 
Ventana Medical Systems, Inc., Tucson, AZ). The stained slides will be evaluated by 
two pathologists (RD and RB) without clinical data to obtain a consensus result. The 
IHC stained TMA slides will then be scanned and analyzed digitally using the Aperio 
® computer assisted image analysis system. A standardized nuclear analysis 
protocol will be used for scoring a minimum of 1,000 cells. The digital scoring will 
be reported as percentage and absolute number of nuclear staining with nuclear 
scores from 0 to 3+ intensity. Endothelial nuclear staining will be used as internal 
control. The Aperio ® results will be compared to the pathologists' consensus 
results and the discrepant cases will be excluded. RB will be consider positive when 
25% or more of the nuclei have a combination of 2+ and 3+ score. Weak positive 
with 10% to 24% of the cells have a combination of 2+ and 3+ score; and negative 
when less than 10% of the cells have a combination of 2+ and 3+ score. 
RB functional analyses via custom array1 
 
cDNA generated from the tumor biopsy and collected CTCs will be used to assess 
functional status of the RB pathway. Probeset intensities for transcripts assayed on 
the RBTARGET will be assessed using robust multichip average (RMA) algorithm in 
Affymetrix Expression Console software. Additional analysis will be performed on 
the processed dataset using high-level programming languages for statistical 
computing, including Rand Matlab. Twenty distinct gene groups represented on the 
RBTARGET array, where genes within each group are highly correlated, will be 
assessed using an Affymetrix U133A Prostate Cancer training dataset. The 
RBTARGET expression profiles for genes in each group will be averaged together, 
resulting in twenty independent feature variables. These twenty feature variables 
will be used in supervised multivariate analysis to determine a linear equation that 
is best able to classify distinct characteristics of prostate cancer and inform 
diagnosis/prognosis. 


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Serum Samples for Androgen panel (testosterone, androstenedione, DHEAS) 
In an analysis of patients receiving abiraterone after prior ketoconazole therapy it 
was observed that a high proportion of patients had undetectable androgen levels 
and that there was an association between lack of response to abiraterone and an 
undetectable level of DHEAS.(Ryan et al Proc ASCO 2011) Further, in the COU-301 
study patients with above median baseline serum androgens were associated with a 
higher PSA response rate after adjusting for treatment and other laboratory 
parameters (i.e., LDH, hemoglobin, ALP; all P < .0001). Thus knowing the androgen 
levels may also be a major factor to the response to abiraterone acetate. 
Serum for androgen profile will be collected prior to the initiation of treatment and 
at end of study. Collect 10 mL of whole blood in a serum separator tube (SST) 
(red/gray top). The tube should be inverted several times to mix clot activator with 
the blood. Allow the blood to clot for a minimum of 30 minutes in a vertical position. 
Observe a dense clot. Centrifuge clotted blood for 15 minutes at 1600 x g, 4°C (or in 
accordance with manufacturer's instructions). The serum should be separated and 
frozen in cyrotubes and stored in -80°C. The samples will be shipped on dry ice and 
shipped overnight mail to the Knudsen lab. Please note the samples can be batched 
shipped but do not ship on Fridays. 
The assay to be used for determining the androgen panel  (testosterone, 
androstenedione, DHEAS and other androgen derivatives) will be performed in the 
laboratory of Dr. Trevor Penning at the University of Pennsylvania and/or a CLIA 
certified laboratory that specializes in ultrasensitive endocrine analyses. 
 Plasma collected for circulating DNA 
Plasma collected for circulating DNA_will be collected prior to the initiation of 
treatment and at End of Study visit. Please see the study-specific laboratory manual 
for further details on plasma sample collection, processing and shipping 
(Laboratory /Correlative Studies Manual). 
6.6.5. 
Shipping of specimens after collection 
Tumor, plasma and blood (serum) samples 
All samples will be shipped to Thomas Jefferson University at the following address: 
Renee de Leeuw 
215-503-8579 
Thomas Jefferson University 
233 South 10th Street, BLSB 1006 
Dr. Karen Knudsen Lab 
Philadelphia, PA 19107 
E-mail: Karen.Knudsen@jefferson.edu 
Adam.Hawkins@jefferson.edu 
renee.deleeuw@jefferson.edu 


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Note: Tissue collected for explant protocol at MSKCC may be shipped to Dr. Slovin's 
laboratory for processing and analysis. 
• 
 Paraffin embedded tumor samples: The paraffin embedded tumor samples can be 
shipped via standard mail, at room temperature. It is requested that efforts be made to 
ship the tumor samples within 30 days of patient enrollment onto the trial. 
• 
Serum and plasma samples for the androgen panel and circulating DNA will be shipped 
frozen on dry ice 
Shipping must occur only Monday-Thursday, and an e-mail or phone call to 
the contact listed on the laboratory contact sheet, alerting her to the 
shipment, is required. A copy of the sample requisition form should also be 
emailed to the PCCTC at pcctc@mskcc.org. 
For further details regarding shipping, please refer to the 
Laboratory /Correlative Studies Manual. 
1. PAXgene tubes will be shipped overnight to: 
MSKCC Laboratory Medicine 
Attn. CTC samples for AA ± Cabazi 
411 E. 67th Street, S-359 
New York, NY 10065 
Tel (212) 639-5969 
Please note, PAXgene tubes can be frozen and batch shipped on dry ice if processed 
per instructions in the Laboratory/Correlatives Studies Manual. Shipping 
reservations must be made to allow delivery within 24 hr of specimen collection, 
and prior to 2:00 PM the next day. Samples must not be drawn or shipped on Friday. 
2. EPIC: Tube will be shipped overnight to: 
Epic Sciences 
Attn. EPIC samples for AA ± Cabazi 
9381 Judicial Drive, Suite 200 San Diego, CA 9221, USA 
Samples should be kept at room temperature at all times. Shipping reservations 
must be made to allow delivery within 24 hr of specimen collection, and prior to 
2:00 PM the next day. 
7. 
THERAPEUTIC MODALITIES 
7.1 
Pharmacokinetics 
7.1.1 
Cabazitaxe/23,24 
A population pharmacokinetic analysis was conducted in 170 patients with solid 
tumors at doses ranging from 10 to 30 mg/m2 weekly or every three weeks. 
Absorption 


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Based on the population pharmacokinetic analysis, after an intravenous dose of 
cabazitaxel 25 mg/m2 every three weeks, the mean Cmax in patients with 
metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end 
of the one-hour infusion (Tmax). The mean AUC in patients with metastatic prostate 
cancer was 991 ng·h/mL (CV 34%). 
No major deviation from the dose proportionality was observed from 10 to 30 
mg/m2 in patients with advanced solid tumors. 
 Distribution 
The volume of distribution (Vss) was 4,864 L (2,643 L/m2 for a patient with a 
median BSA of 1.84 m2) at steady state. 
In vitro, the binding of cabazitaxel to human serum proteins was 89 to 92% and was 
not saturable up to 50,000 ng/mL, which covers the maximum concentration 
observed in clinical trials. Cabazitaxel is mainly bound to human serum albumin 
(82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). The in 
vitro blood-to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, 
indicating that cabazitaxel was equally distributed between blood and plasma. 
 Metabolism 
Cabazitaxel is extensively metabolized in the liver(> 95%), mainly by the CYP3A4/5 
isoenzyme (80% to 90%), and to a lesser extent by CYP2C8. Cabazitaxel is the main 
circulating moiety in human plasma. Seven metabolites were detected in plasma 
(including the 3 active metabolites issued from O-demethylation), with the main one 
accounting for 5% of cabazitaxel exposure. Around 20 metabolites of cabazitaxel are 
excreted into human urine and feces. 
Based on in vitro studies, the potential for cabazitaxel to inhibit drugs that are 
substrates of other CYP isoenzymes (1A2,-2B6,-2C9, -2C8, -2C19, -2E1, -2D6, and 
3A4/5) is low. In addition, cabazitaxel did not induce CYP isozymes in vitro. 
 Elimination 
After a one-hour intravenous infusion [14C]-cabazitaxel 25 mg/m2, approximately 
80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly 
excreted in the feces as numerous metabolites (76% of the dose); while renal 
excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as 
unchanged drug in urine). 
Based on the population pharmacokinetic analysis, cabazitaxel has a plasma 
clearance of 48.5 L/h (CV 39%; 26.4 L/h/m2 for a patient with a median BSA of 1.84 
m2) in patients with metastatic prostate cancer. Following a one-hour intravenous 
infusion, plasma concentrations of cabazitaxel can be described by a three- 
compartment pharmacokinetic model with a-, -, and y- half-lives of 4 minutes, 2 
hours, and 95 hours, respectively. 
 Renal Impairment 


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Cabazitaxel is minimally excreted via the kidney. No formal pharmacokinetic trials 
have been conducted with cabazitaxel in patients with renal impairment. The 
population pharmacokinetic analysis carried out in 170 patients including 14 
patients with moderate renal impairment (30 mL/min:,; CLcr < SO mL/min) and 59 
patients with mild renal impairment (SO mL/min:,; CLcr < 80 mL/min) showed that 
mild to moderate renal impairment did not have meaningful effects on the 
pharmacokinetics of cabazitaxel. No data are available for patients with severe renal 
impairment or end-stage renal disease 
 Hepatic Impairment 
No formal trials in patients with hepatic impairment have been conducted. As 
cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to 
increase the cabazitaxel concentrations. 
 Drug Interactions 
As cabazitaxel is mainly metabolized by CYP3A in vitro, strong CYP3A inducers or 
inhibitors are expected to affect the pharmacokinetics of cabazitaxel. Prednisone or 
prednisolone administered at 10 mg daily did not affect the pharmacokinetics of 
cabazitaxel. 
Adverse Events 
The most common (:::: 10%) Grade 1-4 adverse reactions with cabazitaxel were 
anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, 
vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, 
peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia. 
The most common (:::: 5%) Grade 3-4 adverse reactions in patients who received 
cabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, 
fatigue, and asthenia 
7.1.2 
Abiraterone acetate25 
Following oral administration of abiraterone acetate, the pharmacokinetics of 
abiraterone and abiraterone acetate have been studied in healthy subjects and in 
patients with metastatic CRPC. In vivo, abiraterone acetate is converted to 
abiraterone. In clinical studies, abiraterone acetate plasma concentrations were 
below detectable levels (< 0.2 ng/mL) in > 99% of the analyzed samples. 
Absorption 
Following oral administration of abiraterone acetate to patients with metastatic 
CRPC, the median time to reach maximum plasma abiraterone concentrations is 2 
hours. Abiraterone accumulation is observed at steady-state, with a 2-fold higher 
exposure (steady-state AUC) compared to a single 1000 mg dose of abiraterone 
acetate. 
At the dose of 1000 mg daily in patients with metastatic CRPC, steady-state values 
(mean± SD) of Cmax were 226 ± 178  ng/mL and of AUC were 1173 ± 690 ng.hr/mL. 


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No major deviation from dose proportionality was observed in the dose range of 
250 mg to 1000 mg. 
Systemic exposure of abiraterone is increased when abiraterone acetate is 
administered with food. Abiraterone Cmax and AUC0-oo were approximately 7- and 
5-fold higher, respectively, when abiraterone acetate was administered with a low- 
fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, 
respectively, when abiraterone acetate was administered with a high-fat (57% fat, 
825 calories) meal. Given the normal variation in the content and composition of 
meals, taking abiraterone with meals has the potential to result in increased and 
highly variable exposures. Therefore, no food should be consumed for at least two 
hours before the dose of abiraterone is taken and for at least one hour after the dose 
of abiraterone is taken. The tablets should be swallowed whole with water. 
 Distribution and Protein Binding 
Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and 
alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean± 
SD) is 19,669 ± 13,358 L. In vitro studies show that at clinically relevant 
concentrations, abiraterone acetate and abiraterone are not substrates of P- 
glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp. No studies 
have been conducted with other transporter proteins. 
 Metabolism 
Following oral administration of 14C-abiraterone acetate as capsules, abiraterone 
acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely 
through esterase activity (the esterases have not been identified) and is not CYP 
mediated. The two main circulating metabolites of abiraterone in human plasma are 
abiraterone sulphate (inactive) and N-oxide abiraterone sulphate (inactive), which 
account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes 
involved in the formation of N-oxide abiraterone sulphate and SULT2A1 is involved 
in the formation of abiraterone sulphate. 
 Excretion 
In patients with metastatic CRPC, the mean terminal half-life of abiraterone in 
plasma (mean ± SD) is 12 ± 5 hours. Following oral administration of 14C- 
abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces 
and approximately 5% in urine. The major compounds present in feces are 
unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of 
the administered dose, respectively). 
 Patients with Hepatic Impairment 
The pharmacokinetics of abiraterone was examined in subjects with baseline mild 
(n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, 
respectively) and in 8 healthy control subjects with normal hepatic function. 
Systemic exposure to abiraterone after a single oral 1000 mg dose given under 
fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with 


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Cabazitaxel and Abiraterone Acetate 
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mild and moderate baseline hepatic impairment, respectively. The mean half-life of 
abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic 
impairment and to approximately 19 hours in subjects with moderate hepatic 
impairment. Abiraterone has not been studied in patients with baseline severe 
hepatic impairment (Child-Pugh Class C) 
 Patients with Renal Impairment 
The pharmacokinetics of abiraterone were examined in patients with end-stage 
renal disease (ESRD) on a stable hemodialysis schedule (N=8) and in matched 
control subjects with normal renal function (N=8). In the ESRD cohort of the trial, a 
single 1000 mg abiraterone acetate dose was given under fasting conditions 1 hour 
after dialysis, and samples for pharmacokinetic analysis were collected up to 96 
hours post dose. Systemic exposure to abiraterone after a single oral 1000 mg dose 
did not increase in subjects with end-stage renal disease on dialysis, compared to 
subjects with normal renal function. 
Phase I pharmacokinetic (PK) studies showed increased systemic drug exposure at 
higher doses but antitumor activity was present at all doses tested. Adrenal 
metabolite analysis showed inhibition of CPYl 7 even at low doses of abiraterone 
acetate and a compensatory increase of corticosterone and deoxycorticosterone. 
Data from dose-finding studies indicated that when PK, adrenal CYPl 7 inhibition, 
and efficacy signals are taken into consideration, the 1000-mg dose offered 
consistent pharmacological effects without additional side effects. Therefore, the 
1000-mg dose has been chosen for further efficacy and safety evaluation in this 
Phase II trial. 
Adverse Events 
The most common adverse drug reactions (::::5%) reported in clinical studies were 
joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, 
diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary 
frequency, nocturia, dyspepsia, and upper respiratory tract infection. 
The most common adverse drug reactions that resulted in drug discontinuation 
were aspartate aminotransferase increased, alanine aminotransferase increased, 
urosepsis and cardiac failure (each in <1% of patients taking abiraterone ). 
Adverse reactions and laboratory abnormalities related to mineralocorticoid effects 
were reported more commonly in patients treated with abiraterone than in patients 
treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% 
and fluid retention (edema) 27% versus 18%, respectively. In patients treated with 
abiraterone, Grades 3 to 4 hypokalemia occurred in 5% of patients and Grades 3 to 4 
hypertension was reported in 1% of patients. 
7.2 
Dosage Selected, Preparation, and Schedule of Administration 
Cabazitaxel (Jevtana) will be administered at 25 mg/m2 IV every 3 weeks. The dose of 
cabazitaxel will be calculated as per institutional guidelines. Abiraterone acetate will be 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
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taken daily at 1000mg PO daily in a fasting state along with prednisone 5mg PO BID to 
minimize mineralocorticoid side effects. Cabazitaxel will be supplied by Sanofi S.A. but 
distributed through the vendor Biologics. Abiraterone will be commercially supplied 
through patient's insurance. 
7.2.1 
Supply and Packaging 
 How Supplied 
Cabazitaxel is supplied as a kit containing one single-use vial of Jevtana (cabazitaxel) 
Injection (clear glass vial with a grey rubber closure, aluminum cap and light green 
plastic flip-off cap) and one vial of Diluent for Jevtana Injection (13% (w/w) ethanol 
in water for injection) in a clear glass vial with a grey rubber closure, gold-color 
aluminum cap and colorless plastic flip-off cap. Both items are in a blister pack in 
one carton. 
Injection 60 mg/1.5 mL (NDC 0024-5824-11) is supplied as a kit consisting of the 
following: 
-Jevtana Injection 60 mg/1.5 mL: contains 60 mg cabazitaxel in 1.5 mL polysorbate 
80, 
- Diluent for Jevtana Injection 60 mg/1.5 mL: contains approximately 5.7 mL of 13% 
(w/w) ethanol in water for injection. 
Administration Precautions 
Jevtana is a cytotoxic anticancer drug and caution should be exercised when 
handling and preparing Jevtana solutions, taking into account the use of 
containment devices, personal protective equipment (e.g., gloves), and preparation 
procedures. 
Instructions for Preparation 
Do not use PVC infusion containers or polyurethane infusions sets for preparation 
and administration of Jevtana infusion solution. 
Read this entire section carefully before mixing and diluting. Jevtana requires two 
dilutions prior to administration. Please follow the preparation instructions 
provided below. Note: Both the Jevtana Injection and the diluent vials contain an 
overfill to compensate for liquid loss during preparation. This overfill ensures that 
after dilution with the entire contents of the accompanying diluent, there is an initial 
diluted solution containing 10 mg/mL Jevtana. 
The following two-step dilution process must be carried out under aseptic 
conditions to prepare the second (final) infusion solution. 
Set aside the Jevtana Injection and supplied diluent vials. The Jevtana Injection is a 
clear yellow to brownish-yellow viscous solution, if appropriately stored. 
• 
Step 1 - First Dilution 


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Each vial of Jevtana 60 mg/1.5 mL must first be mixed with the entire contents of 
supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of 
Jevtana. 
When transferring the diluent, direct the needle onto the inside wall of Jevtana vial 
and inject slowly to limit foaming. Remove the syringe and needle and gently mix 
the initial diluted solution by repeated inversions for at least 45 seconds to assure 
full mixing of the drug and diluent. Do not shake. 
Let the solution stand for a few minutes to allow any foam to dissipate, and check 
that the solution is homogeneous and contains no visible particulate matter. It is not 
required that all foam to dissipate prior to continuing the preparation process. 
The resulting initial diluted Jevtana solution (cabazitaxel 10 mg/mL) requires 
further dilution before administration. The second dilution should be done 
immediately (within 30 minutes) to obtain the final infusion as detailed in Step 2. 
• 
Step 2 - Second (Final) Dilution 
Withdraw the recommended dose from the Jevtana solution containing 10 mg/mL 
as prepared in Step 1 using a calibrated syringe and further dilute into a sterile 250 
mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose 
solution for infusion. If a dose greater than 65 mg of Jevtana is required, use a larger 
volume of the infusion vehicle so that a concentration of 0.26 mg/mL Jevtana is not 
exceeded. The concentration of the Jevtana final infusion solution should be 
between 0.10 mg/mL and 0.26 mg/mL. 
Jevtana should not be mixed with any other drugs. 
Remove the syringe and thoroughly mix the final infusion solution by gently 
inverting the bag or bottle. 
Jevtana final infusion solution (in either 0.9% sodium chloride solution or 5% 
dextrose solution) should be used within 8 hours at ambient temperature (including 
the one-hour infusion) or within a total of 24 hours if refrigerated (including the 
one-hour infusion). 
As the final infusion solution is supersaturated, it may crystallize over time. Do not 
use if this occurs and discard. 
Inspect visually for particulate matter, any crystals and discoloration prior to 
administration. If the Jevtana first diluted solution or second (final) infusion 
solution is not clear or appears to have precipitation, it should be discarded. 
Discard any unused portion. 
7.2.2 
Administration 
Cabazitaxel 
The final Jevtana infusion solution should be administered intravenously as an 
approximately one-hour infusion at room temperature. 
Use an in-line filter of 0.22 micrometer nominal pore size during administration. 


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The final Jevtana infusion solution should be used immediately. However, in-use 
storage time can be longer under specific conditions, i.e. 8 hours under ambient 
conditions (including the one-hour infusion) or for a total of 24 hours if refrigerated 
(including the one-hour infusion). 
Abiraterone acetate 
Abiraterone acetate 250 mg, immediate release, uncoated tablets are white to off- 
white, oval-shaped, debossed with AA250 on one side. In addition to 250 mg 
abiraterone acetate, each tablet contains the following compendia! inactive 
ingredients: 
lactose 
monohydrate, 
microcrystalline 
cellulose, 
croscarmellose 
sodium, povidone, sodium lauryl sulfate, magnesium stearate and colloidal silicon 
dioxide. Abiraterone acetate 250 mg tablets are available in high-density 
polyethylene bottles of 120 tablets. 
7.2.3 
Storage requirements 
Cabazitaxel 
Jevtana Injection and Diluent for Jevtana: 
Store at 25°C (77°F); excursions permitted between 15°-30°( (59°-86°F). 
Do not refrigerate. 
Stability of the First Diluted Solution in the Vial: First diluted solution of Jevtana 
should be used immediately (within 30 minutes). Discard any unused portion. 
Stability of the Second (Final) Dilution Solution in the Infusion Bag: Fully prepared 
Jevtana infusion solution (in either 0.9% sodium chloride solution or 5% dextrose 
solution) should be used within 8 hours at ambient temperature (including the 
approximately one-hour infusion), or for a total of 24 hours (including the 
approximately one-hour infusion) under the refrigerated conditions. 
In addition, chemical and physical stability of the infusion solution has been 
demonstrated for 24 hours under refrigerated conditions. As both the first diluted 
solution and the second (final) infusion solution are supersaturated, the solutions 
may crystallize over time. If crystals and/or particulates appear, the solutions must 
not be used and should be discarded. 
Abiraterone acetate 
Store tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C 
(59°F to 86°F). 
7.2.4 
Special handling and disposal 
Cabazitaxel 
Procedures for proper handling and disposal of antineoplastic drugs should be 
followed. Several guidelines on this subject have been published [see References]. 
Any unused product or waste material should be disposed of in accordance with 
local requirements. 


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If Jevtana Injection, first diluted solution, or second (final) dilution for intravenous 
infusion should come into contact with the skin, immediately and thoroughly wash 
with soap and water. If Jevtana Injection, first diluted solution, or second (final) 
dilution for intravenous infusion should come into contact with mucosa, 
immediately and thoroughly wash with water. 
References: 
1.  NIOSH Alert: Preventing occupational exposures to antineoplastic and other 
hazardous drugs in healthcare settings. 2004. U.S. Department of Health and 
Human Services, Public Health Service, Centers for Disease Control and 
Prevention, National Institute for Occupational Safety and Health, DHHS 
(NIOSH) Publication No. 2004-165. 
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling 
Occupational Exposure to Hazardous Drugs. OSHA, 1999. 
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 
3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on 
Handling Hazardous Drugs. Am J Health-Syst Pharm 2006; 63:1172-1193. 
4.  Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and 
biotherapy 
guidelines 
and 
recommendations for 
practice 
(2nd. ed.) 
Pittsburgh, PA: Oncology Nursing Society. 
Abiraterone acetate 
Based on its mechanism of action, abiraterone may harm a developing fetus. 
Therefore, women who are pregnant or women who may be pregnant should not 
handle abiraterone without protection, e.g., gloves. 
7.2.5 
Handling and Dispensing 
Abiraterone and prednisone will be commercially supplied and dispensed. Patients 
will be provided with a diary in which to record their intake of study drug 
(Appendix G). 
Cabazitaxel will be supplied by Sanofi-Aventis and dispensed at the institution of 
registration. Study site personnel will record cabazitaxel administered during this 
trial on a drug dispensation log as per institutional policy at each site. The drug 
dispensation log will contain the following information: 
o patient study identification number 
o date(s) of cabazitaxel administered 
o quantities of cabazitaxel administered 
7.3 
Dose Modifications and Dose Delay 
At each study visit for the duration of their participation in the study, patients will be 
evaluated for adverse events (AEs, all grades), serious adverse events (SAEs), and AEs that 
require study drug interruption or discontinuation. 
If a patient has a greater than 2 week delay in receiving cabazitaxel due to a drug-related 
AE, then cabazitaxel should be discontinued. If a patient has a greater than 2 week delay in 


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receiving abiraterone due to a drug-related AE, then abiraterone should be discontinued. A 
delay greater than 2 weeks and no more than 6 weeks of cabazitaxel due to an event that is 
not related to protocol therapy or after a patient receives limited field palliative radiation is 
acceptable. A delay greater than 2 weeks and no more than 6 weeks of abiraterone due to an 
event that is not related to protocol therapy or after a patient receives palliative radiation is 
acceptable. 
Arm 2 patients who either require that the study drug to be discontinued because of a 
treatment-related AE (as described below) or have a treatment interruption of greater than 
2 weeks for abiraterone acetate or 2 weeks for cabazitaxel due to a treatment-related AE, at 
the investigator's discretion, may continue on the other agent alone until progression as 
long as they have completed 2 cycles of combination therapy. Further details on the dose 
modifications for study drugs are in section 7.3. 
Patients discontinued from the treatment phase of the study for any reason will be 
evaluated approximately 30 days after the last dose of the study drug. Any patient 
hospitalized during the study will be evaluated and treated as per supervising physician and 
appropriate communication reports to the PCCTC will be completed in a timely manner as 
per the FDA guidance for Industry. 
General Rules 
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 ameliorate signs and symptoms including antiemetics for nausea 
and vomiting, anti-diarrheals for diarrhea, and antipyretics, and/or antihistamines for drug 
fever. 
Toxicity will be assessed using the most recent NCICTCAE, v4.0. 
7.3.1 
Dose modification for abiraterone acetate 
I 
For any grade 2 or greater toxicity thought to be related to the abiraterone acetate, 
the dose will be held until grade  1 toxicity. The dose of may be restarted at one 
lower dose level. The dose of abiraterone acetate will not be re-escalated once a 
dose reduction has occurred. Patients may have a maximum of two dose reductions 
of abiraterone acetate. If patient after two dose reductions still has intolerance to 
the abiraterone acetate then the drug should be discontinued. The patient may 
continue on with the cabazitaxel or prednisone without the abiraterone acetate at 
the investigators discretion. 
Asymptomatic laboratory abnormalities would not be considered a SAE unless the 
investigator believes it may potentially impact the participant's safety or unless it is 
specifically addressed separately in the protocol (e.g., hypokalemia and liver test 
abnormalities). 
Dose Level 
Abiraterone acetate 
I Prednisone 
o 
1000 mg daily 
I 5 mg twice daily 
-1 
750 mg daily 
I I 5 mg twice daily 
-2 
500 mg daily 
5 mg twice daily 


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Due to the known side effect of hypokalemia, oral replacement of potassium is to be 
started with Grade 1 hypokalemia. With Grade 3 or 4 hypokalemia, abiraterone 
acetate is to be held until it resolves to :s; Grade 1 and IV potassium replacement is to 
be given with appropriate monitoring. The dose of abiraterone acetate should be 
restarted at one reduced dose level as described above. 
If Grade 2 or higher liver function test abnormalities (AST, ALT or bilirubin) 
develop, the liver function tests should be followed at least weekly until they resolve 
to :5 Grade 1. If Grade 3 liver test abnormalities (AST, ALT or bilirubin) develop, 
abiraterone acetate and any other hepatotoxic drugs should be held until they 
resolve to :s; Grade 1. In the specific case of Grade 3 AST, ALT or bilirubin 
abnormalities, a mandatory dose reduction of abiraterone acetate to 500 mg daily 
must be undertaken, with every 2 week assessments of the liver function tests for at 
least 3 months. If Grade 4 liver test abnormalities (AST, ALT or bilirubin) occur, the 
drug should be permanently discontinued. The PCCTC should also be notified with 
any Grade 3 or 4 liver function test abnormality. If a dose reduction of abiraterone 
acetate below 500 mg daily is required, the abiraterone acetate will be discontinued 
and the cabazitaxel may be continued at the discretion of the investigator. 
Prednisone is included in this regimen primarily as a safety medication to reduce 
the potential incidence of mineralocorticoid excess from abiraterone acetate. For 
this reason, the prednisone cannot be dose reduced or held without holding the 
abiraterone acetate. If Grade 3 or Grade 4 toxicity develops which is known to be 
related to prednisone (e.g. hyperglycemia) and this is believed to potentially impact 
the safety of participation, prednisone must be tapered down and abiraterone 
acetate should be held until the AE resolves to :5 Grade 1. 
7.3.2 
Dose modification for cabazitaxel 
Dose Level 
Cabazitaxel 
0 
25 mg/m2 
-1 
20 mg/m2 
-2 
15 mg/m2 
Patients may have a maximum of two dose reductions and the minimal dose of 
cabazitaxel to be administered is 15 mg/m2 every 3 weeks. The dose, which has 
been reduced for toxicity, must not be re-escalated. Only two dose reductions will be 
allowed per patient. If more than two dose reductions are required per the 
modifications below, the patient should be removed from the study. 
Patients may use G-CSF support at the discretion of the treating physician after cycle 
1 of therapy. If a patient has a greater than 2 weeks delay in receiving cabazitaxel, 
then cabazitaxel should be discontinued. If the cabazitaxel is discontinued for 
intolerable toxicities, patients may continue on the abiraterone acetate and 
prednisone alone until POD or intolerable AEs from the abiraterone acetate. 
 Hematologic toxicity 
The dose cabazitaxel depending on the treatment arm will be modified in case of 
hematological toxicity. Dose modifications are summarized in Table 1. 


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Table 1. Dose modifications for hematological toxicity 
Toxicity 
Grade 2 
Grade 3 
Grade 4 
No dose reduction if isolated and duration :,;7 days. 
Neutropenia 
If not recovered on 
D21, delay** next 
infusion until 
recovery to Grade ::;1 
(neutrophil ;,;1.5 x 
109/L). 
- 1st episode: No dose 
reduction required. 
- znd episode; reduce 
by 1 dose level 
If duration more than 7 days or not recovered on D21 
Delay** next infusion until ANC ;,;1.5 x 109 /Land: 
- 1st episode: reduce the dose 1 dose level and in addition 
administer prophylactic G-CSF treatment in subsequent 
cycles if patient did not received G-CSF. 
- 2nd episode or 1st episode despite prophylactic G-CSF: 
Reduce dose by 1 dose level. 
- 3rd episode or 2nd episode despite prophylactic G-CSF: 
Withdraw from study treatment 
 
Febrile neutropenia 
or neutropenic 
Not applicable 
infection 
Delay** next infusion 
until recovery to 
Grade ::; 1 (platelets 
Thrombocytopenia 
;,;75 x 109/L). 
No dose reduction 
required. 
Delay** next infusion until recovery and ANC ;,;1.5 x 109 /L 
and: 
- 1st episode: reduce the dose 1 dose level and administer 
prophylactic G-CSF treatment in subsequent cycles. 
- 2nd episode: Withdraw from study treatment 
Delay** infusion until platelets ;,;75 x 109 /L 
If Grade 3 without delay, no dose reduction required. 
If Grade 4 with or without delay, or Grade 3 with delay 
- 1st episode: Reduce dose by 1 dose level. 
- 2nd episode: Withdraw from study treatment in case of 
recurrence 
 
** maximum of 2 weeks delay, otherwise the patient will discontinue cabazitaxel 
Blood counts will be performed in case of fever or infection. Blood count should be 
monitored weekly for the first cycle to determine if G-CSF or dosage modification is 
needed. 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 and use of G-CSF should be considered according to ASCO 
guidelines. 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). 
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. 


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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: 
pruritus, flushing, rash. 
o Consider decreasing the rate of infusion until recovery of 
symptoms, stay at bedside 
o Complete cabazitaxel infusion at the initial planned rate. 
Moderate: Generalized 
pruritus, more severe 
flushing or rash, mild 
dyspnea, hypotension 
with systolic B8.P. >80 
mmHg 
o Stop cabazitaxel infusion 
o  Give IV diphenhydramine 50 mg and/or !VIV dexamethasone 
10mg 
o  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. 
o Re-administer premedication regimen as described in Section 
7.2 when cabazitaxel is reinfused more than 3 hours after the 
interruption 
o Administer cabazitaxel over 2 hours for all subsequent 
infusions 
Severe:bronchospasm, 
generalized urticaria, 
hypotension with systolic 
B8.P.:::;80 mmHg, 
angioedema. 
o Stop cabazitaxel infusion 
o Give IV diphenhydramine 50 mg and/or IV dexamethasone 10 
mg 
o Add epinephrine** or bronchodilators and/or IV plasma 
expanders if indicated 
o  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 
o Re-administer premedication regimen as described in Section 
7.2 when cabazitaxel is reinfused more than 3 hours after the 
interruption 
o Administer cabazitaxel over 2 hours for all subsequent 
infusions 
o 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 


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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 
:51. Treatment may then be resumed, but the dose of cabazitaxel should be reduced 
by 1 dose level for all subsequent doses. In case of Grade 4 stomatitis, the patient 
will be withdrawn from treatment with cabazitaxel. 
 Diarrhea 
No prophylactic treatment for diarrhea is recommended in Cycle 1. However, 
following the first episode of diarrhea, the patient should be treated with 
rehydration or antidiarrheal medications as needed. In case of Grade 3 diarrhea or 
persisting 
diarrhea 
despite 
appropriate 
medication, 
fluid 
and 
electrolytes 
replacement, delay treatment until improvement or resolution, then reduce the dose 
by 1 dose level. If despite dose reduction, diarrhea still occurs at Grade 3, the 
patient will be withdrawn from treatment with cabazitaxel. 
 Renal function 
No dose adjustment is necessary in patients with renal impairment not requiring 
hemodialysis. Patients presenting with end-stage disease (creatinine clearance 
CLrn<15mL/min/1.73m2), should be monitored carefully during treatment [see 
Clinical Pharmacology (12.3]. 
 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 efforts 
should be undertaken to document the cause (e.g., urine cultures, urinary tract 
ultrasound, and if no cause identified cystoscopy with or without biopsy). 
 Peripheral neuropathy 
Dose modification should be performed as follows: 
o Grade :51: No change 
o Grade 2: Retreat with reduced dose (reduce by 1 dose level) 
o Grade 3: Patient will be withdrawn from treatment with cabazitaxel 
 Liver toxicity 
Cabazitaxel is extensively metabolized in the liver. Patients with mild hepatic 
impairment (total bilirubin > 1 to :5 1.5 x ULN or AST > 1.5 x ULN) should have 
cabazitaxel dose reduced to 20mg/m2. Patients with moderate hepatic impairment 


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(total bilirubin > 1.5 to :,; 3.0 ULN and AST = any) should have cabazitaxel dose 
reduced to 15 mg/m2. Administration of cabazitaxel to patients with mild and 
moderate hepatic impairment should be undertaken with caution and close 
monitoring of safety [see Clinical Pharmacology (12.3)). Cabazitaxel is 
contraindicated in patients with severe hepatic impairment (total bilirubin > 3 x 
ULN). 
Other Toxic Effects 
For <! Grade 3 toxicities except fatigue, local reaction, fluid retention, anemia and 
other toxicities that merely are uncomfortable but do not cause serious morbidity to 
patients, chemotherapy should be held for a maximum of 2 weeks from the planned 
date of reinfusion until resolution to :,; Grade 1, then reinstituted, if medically 
appropriate. A dose reduction of subsequent doses (1 dose level) will be left to the 
investigator's judgment. These patients will be withdrawn from study treatment if 
>2 dose reductions are needed. 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. 
7.4 
Removing Patients from the Protocol 
In the absence of treatment delays because of AEs, treatment will continue until one of the 
following criteria applies: 
• patient decides to withdraw from the study 
• disease progression 
• study closure 
• symptomatic disease progression at any time 
• objective clinical disease progression 
• intercurrent illness that prevents further administration of treatment 
• unacceptable AE(s) that may or may not be directly related to treatment but that, in the 
judgment of the treating physician, makes it dangerous for the patient to be retreated 
• general or specific changes in the patient's condition that render the patient unacceptable 
for further treatment, in the judgment of the investigator 
Because an excessive rate of withdrawals can render the study not interpretable, 
unnecessary withdrawal of patients should be avoided. When a patient discontinues 
treatment early, the investigator should make every effort to contact the patient and to 
perform a final evaluation. The reason(s) for withdrawal should be recorded. 
7.5 
Concomitant Medications and Supportive Care 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, 
over-the-counter medications, and alternative therapies must be documented on the CRF. 
The principal investigator should be alerted if the patient is taking any agent found in 
Appendix B (a listing of medications with the potential for drug-drug interactions). 
7.5.1 
CYP450 system 
Abiraterone causes inhibition of P450 CYPs 2C19, 2D6 and 1A2. So any medications 
known to be metabolized by the P 450 system should be used with caution. 
Abiraterone is thought to be a weak inhibitor of these enzymes. 


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7.5.2 
Anticoagulants 
Anticoagulants should be held prior to biopsy to obtain tumor to check the RB status 
of the tumor. 
7.5.3 
Supportive care 
Use of growth factors will be should be utilized as needed to reduce complications 
from cabazitaxel after first cycle of therapy as per ASCO guidelines. 
8. 
SAFETY EVALUATION AND REPORTING 
8.1 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a research patient during a 
clinical study or within 30 days post-treatment, regardless of causality. This includes 
adverse clinical or laboratory findings, any adverse drug reaction (ADR), an illness with 
onset during the study, or an exacerbation of preexisting illness or condition. 
8.2 
Recording and Grading 
8.2.1 
Recording 
All observed or volunteered AEs, regardless of treatment group, severity, suspected causal 
relationship, expectedness, or seriousness will be recorded. The NCI CTCAE v4.0 will be 
used for recording and grading AEs. 
Follow-up of AEs should continue until the event and any sequela resolve or stabilize at a 
level acceptable to the investigator and the lead site/sponsor or medical monitor. 
A clinically significant change in a physical examination finding or an abnormal test result 
(i.e., laboratory, x-ray, EKG) should be recorded as an AE, if it: 
o is associated with accompanying symptoms 
o requires additional diagnostic testing or medical or surgical intervention 
o leads to a change in study dosing or discontinuation from the study 
o requires additional concomitant drug treatment or other therapy, or 
o is considered clinically significant by the investigator or sponsor. 


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An abnormal test result that is subsequently determined to be in error does not require 
recording as an AE, even if it originally met one or more of the above criteria. 
8.2.2 
Grading severity 
All AEs will be graded for intensity on a scale of 0 to 5. Severity grades will be recorded and 
based on the CTCAE version 4.0. 
8.2.3 
Attributing causality 
After grading for severity, the investigator must evaluate all clinical AEs and abnormal 
laboratory values for possible causal relationship to the study drugs. Causality attribution 
will be classified as either "related" or "non-related". 
Abnormal laboratory values of clinical significance that were present at baseline and 
did not change in severity or frequency during experimental therapy or intervention 
and those that can obviously be attributed to underlying disease will be recorded as 
unrelated and will not be considered when evaluating the maximum tolerated dose 
(MTD). 
8.3 
Unexpected Adverse Events 
An unexpected AE is any event not associated by nature or intensity with the investigational 
agent under study. The Comprehensive Adverse Event and Potential Risks (CAEPR) list 
provides a single, complete list of reported and potential AEs associated with an agent using 
a uniform presentation of events by body system. In addition to the comprehensive list, a 
subset, the Agent Specific Adverse Event List (ASAEL), contains events that are considered 
expected for expedited reporting purposes only. A listing of expected and unexpected 
events for the agent(s) under investigation for cabazitaxel and abiraterone acetate in this 
study may be found in Appendix E. 
8.4 
Serious Adverse Events and Serious Adverse Drug Reactions 
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 sponsor that the product may have caused the event. 


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Unexpected Adverse Drug Reaction: An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information (e.g., Investigator's Brochure for an 
unapproved investigational product or 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. 
All SAEs that occur any time a patient is on study (i.e., as soon as the informed consent has 
been signed) or within 30 days of the last dose of cabazitaxel or abiraterone acetate must be 
recorded, regardless of the suspected relationship to the drugs. Any SAE occurring more 
than 30 days after the last dose of the study drugs must be recorded if a causal relationship 
to them is suspected. 
8.4.1 
Progression of malignancy 
Progression of a patient's malignancy should not be considered an AE, unless in the 
investigator's opinion, study treatment resulted in an exacerbation of the patient's 
condition. If disease progression results in death or hospitalization while on study 
or within 30 days of the last dose, progressive disease will be considered an SAE. 
8.4.2 
Life-threatening events 
A life-threatening event is any AE that places the patient at immediate risk of death 
from the reaction as it occurs. It is not a reaction that, had it occurred in a more 
severe form, might have caused death. 
8.4.3 
Hospitalization or prolongation of hospitalization 
Hospitalization encompasses any inpatient admission (greater than 24 hours) 
resulting from a precipitating, treatment-emergent AE. For chronic or long-term 
patients, inpatient admission also includes transfer within the hospital to an acute 
or intensive care inpatient unit. Hospitalizations for administrative reasons or a 
non-worsening preexisting condition should not be considered AEs (e.g., admission 
for workup of a persistent pretreatment laboratory abnormality, yearly physical 
exam, protocol-specified admission, elective surgery). Preplanned treatments or 
surgical procedures should be noted in the baseline documentation. Hospitalization 
because of an unplanned event will be deemed an SAE. 
Prolongation of hospitalization is any extension of an inpatient hospitalization 
beyond the stay anticipated or required for the original reason for admission. 
8.4.4 
Significant disability 
Disability is a substantial disruption of the patient's ability to conduct normal life 
functions. 
8.4.5 
Congenital anomaly 
If the female partner of a male patient becomes pregnant during the course of the 
study, the treating physician must be notified immediately. All confirmed 
pregnancies must be immediately reported to the lead investigator and sponsor and 
recorded in the consortium database. All pregnancies will be followed until 
resolution (i.e., voluntary or spontaneous termination or birth) and assessed for 
congenital anomalies and birth defects. 


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8.4.6 
Medically significant event 
An event that is not fatal or life-threatening and that does not necessitate 
hospitalization may be considered serious if, in the opinion of the investigator, it 
jeopardizes the patient's status and might lead to medical or surgical intervention to 
prevent any of the above outcomes. Such medically significant events could include 
allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasias that do not result in inpatient hospitalization, vasculitis, 
"generalized edema", or the development of drug dependency or abuse. 
8.5 
Reporting Serious Adverse Events 
8.5.1 
Reporting serious adverse events 
All SAEs, events determined to be medically significant by the treating Investigator, 
and unknown reactions or unexpected events should be reported to the lead 
site/sponsor and the PCCTC within 24 hours of knowledge of the event using the 
contact information below. The PCCTC will provide an initial notification of SAEs to 
Sanofi within 1 business day of PCCTC awareness or identification of the event. 
The initial report for each SAE or death should include the following information: 
o protocol# and title 
o study identification number, sex, age 
o date the event occurred 
o description of the SAE 
o causal relationship to the study drug 
The PCCTC SAE Report Form (Appendix J) will be used for reporting each SAE and 
should be submitted to the PCCTC within 3 calendar days oflearning of the event. 
When a life-threatening event or death is unforeseen and indicates participants or 
others are at increased risk of harm, participating sites should notify PCCTC as soon 
as possible but within 24 hours of the time the participating site becomes aware of 
the event. Severity, causality, action taken, concomitant medications, outcome, etc 
should be reported to the PCCTC as soon as possible. 
Follow-up of adverse events should continue until the event and any sequela resolve 
or stabilize at a level acceptable to the investigator. 
The PCCTC will facilitate all SAE reporting to the MSKCC IRB/PB and Sanofi within 5 
calendar days. PCCTC is responsible for informing all participating sites about all 
unexpected SAEs that are either possibly, probably, or definitely related to the study 
intervention within 15 days of receiving the stamped SAE report from the MSK 
IRB/PB. PCCTC is responsible for informing all participating sites within 24 hours or 
on the next business day about a life-threatening event or death that is unforeseen 
and indicates participants or others are at increased risk of harm. 
SAE contact information for the PCCTC, lead site/sponsor is listed below: 
Lead Site Study Pl: 


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Susan Slovin, MD, PhD 
Memorial Sloan Kettering Cancer Center 
Genitourinary Oncology Service 
1275 York Avenue 
New York, NY 10065 
slovins@mskcc.org 
PCCTC: 
Prostate Cancer Clinical Trials Consortium 
Phone: 646-888-0434/646-422-4383 
Email:  PCCTC@mskcc.org 
Sanofi Pharmacovigilance Contact: 
Fax: 908-547-8000 
E-mail: CL-CPV-Receipt@sanofi.com 
8.6 
Safety Reports 
The PCCTC will distribute outside safety reports to the participating sites immediately 
upon receipt. Participating sites are responsible for submitting safety reports to their local 
IRB/PB as per their local IRB guidelines. All local IRB approvals/acknowledgments of safety 
reports must be sent to the PCCTC upon receipt. 
8.7 
Unanticipated Problems 
Unanticipated problems involving risks to participants or others (UPs) are defined as any 
incident, experience or outcome that meets all of the following criteria: 
• 
 Unanticipated (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB- 
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; and 
• 
 Related or possibly related to participating in the research (possibly related means 
there is a reasonable probability that the incident, experience or outcome may have 
been caused by procedures involved in the research); and 
• 
Suggests that the research place participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
Participating sites are responsible for reporting all UPs to PCCTC as soon as possible but 
within  3 calendar days oflearning of the event. UPs that are SAEs should be reported to 
PCCTC via SAE Report form as per Appendix D. All other UPs should be reported to PCCTC 
in a memo signed by the site PI. 
PCCTC is responsible for submitting UPs to the MSK IRB/PB according to institutional 
guidelines. In addition, PCCTC is responsible for notifying participating sites of all non-SAE 
UPs that may affect the sites. 


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9. 
CRITERIA FOR OUTCOME ASSESSMENT /THERAPEUTIC RESPONSE 
9.1 
Outcome Assessment 
All baseline evaluations will be performed as closely as possible to the beginning of 
treatment. For subsequent evaluations, the method of assessment and techniques will be 
the same as those used at baseline. 
9.1.1 
Primary Objective 
9.1.1.1 To determine the radiographic progression free survival (rPFS) in patients 
treated with abiraterone acetate\prednisone with and without cabazitaxel in 
patients with chemotherapy nai:ve CRPC. 
9.1.1.2 Secondary Objectives 
9.1.1.2.1 
To determine PSA progression free survival (PSA PFS) in patients 
treated with abiraterone acetate\prednisone with and without 
cabazitaxel in patients with chemotherapy nai:ve CRPC 
9.1.1.2.2 
To determine the proportion of patients with measurable disease 
regression based on the RECIST treated with abiraterone acetate with 
and without cabazitaxel in patients with chemotherapy nai:ve CRPC. 
9.1.1.2.3 
To determine the overall toxicity and survival for patients treated with 
abiraterone acetate with and without cabazitaxel in patients with 
chemotherapy nai:ve CRPC. 
9.1.1.2.4 
To determine the proportion of patients that have an objective response 
using the RECIST and post-therapy PSA decline using a waterfall plot in 
patients that are treated with cabazitaxel after progression on the 
abiraterone/prednisone alone arm. 
9.2 
Therapeutic Response 
Response and progression will be evaluated in this study using a combination of the 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee (Table 4) and the guidelines for prostate cancer endpoints developed 
by the Prostate Cancer Clinical Trials Working Group (PCWG2, Table 5).26 
Patients will need to be reevaluated for response every cycle according to the guidelines 
below. 
9.2.1 
PSA 
Perform PSA testing at a minimum of 1-week intervals with the threshold PSA level 
at 2.0 ng/mL. To report PSA-based outcomes, PCWG2 recommends that the percent 
of change in PSA from baseline to 12 weeks (or earlier for those who discontinue 
therapy) and the maximum decline in PSA that occurs at any point after treatment 
be reported for each patient using a waterfall plot. Because the rate of rise has 
shown prognostic significance, estimate a pretreatment PSA doubling time (PSA-DT) 
if at least 3 values are available, but do not delay either treatment or enrollment 


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onto a trial simply to estimate PSA-DT. Because declines in serum PSA, if they occur, 
may not do so for several weeks, PSA measurements obtained during the first 12 
weeks should not be used as the sole criterion for clinical decision making.zs 
9.2.2 
Measurable disease 
According to RECIST, measurable disease is defined as at least 1 lesion> 20 mm in 
its longest diameter as measured with conventional techniques (i.e., CT [nonspiral 
or non-helical], MRI, physical exam) or> 10 mm as measured with spiral CT scan. All 
tumor measurements will be taken using a ruler or calipers and recorded in 
millimeters (or decimal fractions of centimeters). 
9.2.3 
Non-measurable disease 
Following RECIST, all other lesions (or sites of disease) will be considered non- 
measurable disease. This includes small lesions (longest diameter< 20 mm with 
conventional techniques or< 10 mm using spiral CT scan) and any of the following: 
o bone lesions 
o ascites 
o pleural or pericardia! effusion 
o lymphangitis cutis or pulmonitis 
o abdominal masses that are not confirmed and followed by imaging techniques 
o cystic lesions 
o lesions occurring within a previously irradiated area unless they are 
documented as new lesions since the completion of radiation therapy 
Note: If only a single, asymptomatic bone lesion is present at baseline, and 
will be irradiated, the metastatic nature of this lesion must be confirmed by 
x-ray, CT, or MRI. 
9.2.4 
Target (nodal and visceral) lesions 
Following RECIST, progression in a nodal or visceral site (i.e., liver and lung) is 
sufficient to document disease progression. The presence or absence of nodal and 
visceral disease before and after treatment should be recorded separately. 
All measurable lesions (up to a maximum of 5 lesions per organ and 10 lesions in 
total) will be identified as target lesions to be measured and recorded at baseline. 
The target lesions should be representative of all involved organs. Target lesions 
will be selected on the basis of size (i.e., the largest area) and suitability for accurate, 
repeated measurements (either by imaging techniques or clinically). The sum of the 
longest diameter (LD) of all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as a reference by which to 
characterize the objective tumor response. 
Because small lymph nodes are difficult to measure accurately and may not be 
malignant, the greatest diameter of a lymph node must measure at least 2 cm by 
spiral CT to be considered a target lesion.zs 
9.2.5 
Bone lesions 


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When the bone scan is the sole indicator of progression, disease progression in bone 
is defined as 2 or more new lesions seen on bone scan compared with a prior scan 
for used trial entry.zs 
In situations where scan findings suggest a flare reaction or where new lesion(s) 
may represent trauma, confirm these results with other imaging modalities (e.g., 
MRI or fine-cut CT). If many new areas of uptake are observed, confirmation is 
generally not necessary. 
9.2.6 
Non-target lesions 
All other lesions (or sites of disease) will be identified as nontarget lesions and 
recorded at baseline. Nontarget lesions will include measurable lesions that exceed 
the maximum number per organ (5) or total of all involved organs (10), as well as 
nonmeasurable lesions. The presence or absence of these lesions will be recorded 
on the CRF and should be evaluated at the same assessment time points as all target 
lesions. 
9.2.7 
New lesions 
The appearance of up to 10 new measurable lesions should be recorded. Each new 
lesion should be reassessed using the same imaging modality at each time point. If 
measurable, the LD of each new lesion should be recorded in the CRF and the sum 
LD of new and old lesions should be calculated. See Table 4 for a description of the 
determination of progression based on the presence of new lesions. 
Note: The appearance of a new lesion does not by itself satisfy the criteria for 
confirmed progressive disease. Rather, the tumor burden imposed by the new 
lesions must be evaluated within the context of the total tumor burden (i.e., 
preexisting plus new lesions). Confirming progression in target lesions, non- 
target (i.e., other than bone) lesions, and bone lesions requires 2 assessment 
time points. The first must occur at Week 9 (or later) and the second occurring 
at least 6 weeks after the first. Progression declared at the first time point 
remains unconfirmed unless assessments at the second time point demonstrate 
continuing  or  worsening  progression,  as  described  in  Section  9.4. 
9.3 
Response Criteria for Control/Relieve/Eliminate Endpoints 
9.3.1. 
Measurable soft-tissue lesions 
When evaluating soft-tissue lesions, the definitions in Table 2 apply. 
Table 2. REC/ST response criteria for target (soft-tissue) lesions 
Response 
Complete response (CR) 
Partial response (PR) 
Progressive disease (PD) 
Stable disease (SD) 
Evaluation of Soft-Tissue Lesions 
the disappearance of clinical and radiological evidence of all target 
lesions and normalization of tumor marker levels 
a decrease from baseline<'= 30% in the sum of the LD of all target 
lesions 
an increase <'= 20% in the sum of the LD of all target lesions based 
on the smallest sum LD since treatment started or the appearance 
of one or more new lesions or the appearance of new lesions 
neither sufficient shrinkage to qualify for PR nor sufficient increase 
 


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to qualify for PD based on the smallest sum LD recorded since 
treatment started 
Abbreviations: LD, longest diameter. 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (e.g., fine 
needle aspirate or biopsy) before confirming the complete response status. 
Changes in nodal and visceral sites should be recorded and reported separately, and 
lymph nodes in the pelvis must measure at least 2 cm in greatest diameter to be 
considered target lesions. Complete elimination of disease at a particular site should 
be recorded separately. Any favorable change should be confirmed using a second 
follow-up scan. 
9.3.2 
PSA 
As long as patient safety is the primary concern, in the absence of other indicators of 
disease progression, therapy should not be discontinued solely on the basis of a rise 
in PSA. 
For each patient, use a waterfall plot to report the percent change in PSA from 
baseline to 12 weeks (or earlier for those who discontinue therapy) and the 
maximum decline in PSA that occurs at any point after treatment. 
9.3.3 
Bone 
Record post-treatment changes as either "no new lesions" or "new lesions" as 
indicated on the forms in appendix K. 
In the absence of clearly worsening soft-tissue (nodal and visceral) disease or 
disease-related symptoms, progression at the first scheduled assessment should be 
confirmed on a second scan performed 6 or more weeks later. In the rare case 
where visible lesions disappear, this too should be confirmed. 
9.3.4 
Non-target lesions 
When assessing non-target lesions, the definitions in Table 3 will apply. 
Table 3. RECIST response criteria for non-target lesions 
Response 
Complete response (CR) 
Incomplete response/ 
stable disease (SD) 
Progressive disease (PD) 
Evaluation of Non-target Lesions 
the disappearance of all non-target lesions and normalization of 
tumor marker levels 
the persistence of one or more non-target lesions and/or 
maintenance of tumor marker levels above the normal limits 
the appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
A clear progression of non-target lesions only is exceptional. In such circumstances, 
the progression status, as assigned by the investigator, may be reviewed by a PCCTC 
panel. 


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9.3.5 
Evaluating best overall response 
The best overall response is the best response recorded from the start of treatment 
until either disease progression or recurrence. The investigator's determination of 
best overall response will be based both on response criteria and on confirmation 
criteria. To be assigned a status of partial response or complete response, changes in 
tumor measurements must be confirmed by repeat assessment performed 
4-6 weeks after the criteria for response are first met. To confirm stable disease, 
follow-up measurements must meet SD criteria at a minimum interval of 4 weeks 
after SD was first documented. Table 4 can be used as an assessment tool. 
Table 4. Assessing Overall Response 
Target Lesions 
Non target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. 
Patients with global deterioration of health status who require treatment to be 
discontinued without objective evidence of disease progression should be classified 
as having symptomatic deterioration. Every effort should be made to document 
their objective progression, even after discontinuing treatment. 
Patients who do not have tumor response assessment due to rapid progression or 
toxicity will be considered non-responders, will be included in the denominator for 
the response rate, and will be classified into one of the categories listed below: 
o death attributed to disease progression 
o early discontinuation attributed to disease progression 
o death attributed to drug toxicity 
o early discontinuation attributed to drug toxicity 
Note: If a patient receives subsequent therapy before tumor progression is 
documented, the reason for changing therapy must be reported. Reasons include 
clinical progression, drug toxicity, or secondary therapy for maintaining tumor 
response 
9.4 
Confirmatory Measures/Duration of Response 
9.4.1 
Confirming time-to-event outcomes 
Any post-treatment change in disease status, be it favorable or unfavorable should 
be confirmed using a second assessment. 


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9.4.2 
Duration of overall response 
Duration of overall response is measured from the time when partial response or 
complete response is first noted until the date when recurrent or progressive 
disease is objectively documented. Duration of overall complete response is 
measured from the time the criteria for complete response are first met until the 
first date that recurrent disease is objectively documented. Duration of stable 
disease is measured from the start of treatment until the criteria for progression are 
met. 
9.4.3 
Radiographic Progression-free survival 
Radiographic progression-free survival (rPFS) is a composite endpoint defined as 
the time from treatment start to disease progression in bone or soft-tissue, or 
death, whichever occurs first. All assessments of disease should be collected at the 
same time interval (e.g., bone scan, CT scan, and PSA). In addition to PSA, confirm 
post-treatment changes in measurable target lesions, radionuclide bone scans, and 
symptoms. 


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Table 5. Prostate Cancer Clinical Trials Working Group Outcome Measures26 
PSA 
Variable 
Control/Relieve/Eliminate Endpoints 
Record the percent change from baseline 
(rise or fall) at 12 weeks and, separately, 
the maximal change (rise or fall) at any 
time using a waterfall plot 
Prevent/Delay Endpoints 
Decline from baseline: record time from 
start of therapy to first PSA increase that is 
~25% and ~2 ng/mL above the nadir, and 
which is confirmed by a second value 3 or 
more weeks later (i.e., a confirmed rising 
trend)t 
Recording the duration of PSA decline of 
little value 
No decline from baseline: PSA progression 
~25% and ~2 ng/mL after 12 weeks 
Soft-tissue lesions 
Bone 
Use RECIST with caveats: 
Only report changes in lymph nodes that 
were ~ 2 cm in diameter at baseline 
Record changes in nodal and visceral soft 
tissue sites separately 
Record complete elimination of disease at 
any site separately 
Confirm favorable change with second 
scan 
Record changes using waterfall plot 
Record outcome as either new lesions or 
no new lesions 
First scheduled reassessment: 
No new lesions: continue therapy 
New lesions: perform a confirmatory scan 
6 or more weeks later 
Confirmatory scan: 
No new lesions: continue therapy 
Additional new lesions: progression 
Subsequent scheduled reassessments: 
No new lesions: continue 
New lesions: progression 
Use RECIST criteria for progression, with 
additional requirement that progression at 
first assessment be confirmed by a second 
scan 6 or more weeks later 
Note that for some treatments, a lesion may 
increase in size before it decreases 
 
 
 
 
 
The appearance of~ 2 new lesions, and, for 
the first reassessment only, a confirmatory 
scan performed 6 or more weeks later that 
shows at least 2 or more additional new 
lesions 
The date of progression is the date of the 
first scan that shows the change 
Symptoms 
Consider independently of other outcome measures 
Document pain and analgesia at entry with a lead-in period and measure repeatedly at 3- 
to 4-week intervals 
Perform serial assessments of global changes in HRQOL, urinary or bowel compromise, 
pain management, additional anticancer therapy 
Ignore early changes (~12 weeks) in pain or HRQOL in absence of compelling evidence of 
disease progression 
Confirm response or progression of pain or HRQOL endpoints ~3 weeks later 
 
Abbreviations: PSA, prostate-specific antigen; HRQOL, health-related quality of life.tParticularly important when anticipated effect on PSA is 
delayed or for biologic therapies. 


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10. 
DATA REPORTING AND REGULATORY REQUIREMENTS 
10.1 
Data Collection and Management 
Data collected during this study will be entered into a secure database. 
10.1.1 Electronic case report forms (eCRFs) 
The participating sites will enter data remotely into electronic Case Report Forms 
(eCRFs) using the internet based PCCTC Caisis Electronic Data Capture (EDC) 
system. Completion guidelines will be created by the PCCTC for the collection of all 
study data. Access and training for PCCTC Caisis EDC will be made available to 
participating sites upon local regulatory approval. The participating site PI is 
responsible for ensuring eCRFs are completed accurately and in a timely manner. 
10.1.2 Source documents 
Source documentation refers to original records of observations, clinical findings 
and evaluations that are subsequently recorded as data. Source documentation will 
be made available to support the subject's research record. Source documentation 
must include a minimum of two identifiers to allow for data verification. MSK will 
maintain the confidentiality of any subject-identifiable information it may 
encounter. 
10.1.3 Record retention 
The investigator will maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. 
The investigator will ensure that all regulatory documents and participating site IRB 
correspondences are maintained in an onsite regulatory binder. After study closure, 
the investigator will maintain all source documents and study-related documents.. 
Records are to be retained and securely stored until the later of: (a) two (2) years 
following the date a New Drug Application is approved for the Study Drug that is the 
subject of the Clinical Trial; or (b) two (2) years after the Investigational New Drug 
Application for such Study Drug is terminated or withdrawn, or such longer period 
of time as may be required by Participant policies, applicable laws, rules or 
regulations. 
10.1.4 Source Documentation Submission for Registration at Participating Sites 
Participating sites should email any source documentation that corresponds to data 
entered at registration to the PCCTC at  PCCTC@mskcc.org within 24 hours (see 
Section 4.2.1). 
10.1.5 
Data Submission Timelines 
All study data should be transmitted to the PCCTC within 14 days of visit except for 
SAE submission (see section 8.5) as described in the Data Management Plan. 
10.1.6 
Data Review and Queries 
The PCCTC will review data and source documentation as it is submitted. Data will 
be monitored and source verified as necessary and discrepancies will be sent as 
queries to the participating sites. In addition, the PCCTC will review data for logic, 


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consistency, and obvious anomalies. Queries will be sent by the PCCTC to 
participating sites as needed. 
Participating sites should respond to data queries within 14 days ofreceipt. 
10.2 
Study Monitoring and Quality Assurance 
10.2.1 Data and Safety Monitoring 
The Data and Safety Monitoring Plans (DSMP) at Memorial Sloan Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001. The 
plans address the new policies set forth by the NCI in the document entitled "Policy 
of the National Cancer Institute for Data and Safety Monitoring of Clinical Trials" 
which can be found at: http://www.cancer.gov/clinicaltrials/conducting/dsm- 
guidelines/pagel. The DSMPs at MSKCC were established and are monitored by the 
Office of Clinical Research. The MSKCC DSMPs can be found on the MSKCC Intranet 
at: 
http://inside2/ clinresearch/Documents/MSKCC%2 0Data%20and%2 0Safety%2 0M 
onitoring%20Plans.pdf. 
There are several different mechanisms by which clinical trials are monitored for 
data, safety, and quality. There are institutional processes in place for quality 
assurance (e.g., protocol monitoring, compliance and data verification audits, 
therapeutic response, and staff education on clinical research quality assurance) 
and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials 
programs. There are several committees: Data and Safety Monitoring Committee 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board 
(DSMB) for Phase III clinical trials, report to the MSKCC Research Council and 
Institutional Review Board. As a moderate risk trial, this study will be monitored by 
DSMC twice per year. 
Since therapeutic efficacy is a stated primary objective, all sites participant's 
responses are subject to review by MSKCC's Therapeutic Response Review 
Committee (TRRC). Radiology and additional lab reports will need to be obtained 
from the participating sites for MSKCC TRRC review and confirmation of response 
assessment. These materials must be sent to MSKCC promptly upon request. 
10.2.2 Data Monitoring and Quality Assurance 
In addition to review by DSMC, the PCCTC will conduct regularly scheduled 
monitoring visits. 
Registration reports will be generated by the PCCTC to monitor subject accruals and 
the completeness of registration data. Routine data quality reports will be generated 
to assess missing data and inconsistencies. Accrual rates and the extent and 
accuracy of evaluations and follow-up will be monitored periodically throughout the 
study period, and potential problems will be brought to the attention of the 
Principal Investigator for discussion and action. 


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Each site participating in the accrual of participants to this protocol will be 
monitored at a minimum of 10% of all subjects, but at least 2 from each site, will be 
100% source data verified by the PCCTC. Monitoring will occur once shortly after 
initiation of subject recruitment at a site, annually during the study (or more 
frequently if indicated), and at the end or closeout of the trial, for protocol and 
regulatory compliance, data verification and source documentation. Monitoring 
visits may be accomplished in one of two ways: (1) sending source documents and 
research records for selected patients from participating sites to the PCCTC for 
audit, or (2) on-site monitoring of selected patient records at participating sites. 
The monitoring visit will include a review of source documentation to evaluate 
compliance for: 
1.  Regulatory /IRB compliance (review of current protocol and amendments, 
Informed consent documents and procedures, annual continuing review reports, 
AEs/SAEs) 
2. Protocol defined treatment compliance 
3. Subject records 
• 
 Each subject is audited to reviewed to determine that there is a signed and 
dated consent form 
• 
Adherence to eligibility criteria 
• 
Baseline, on study and follow-up protocol testing 
• 
eCRF completion 
Monitoring visit findings will be reviewed and disseminated to the site Pis and staff. 
In addition, each participating site accruing participants to this protocol will be 
audited by MSKCC for protocol and regulatory compliance, data verification and 
source documentation. Audits of selected participant records may be conducted on- 
site or remotely. 
Audits will be conducted annually at minimum, and more often if significant and/or 
repeated findings are identified during monitoring visits. The number of 
participants audited will be determined by the outcome of monitoring visits and 
complexity of the protocol. 
Each audit will be summarized and a final report will be sent to the PI at the audited 
participating site within 30 days of the audit. The report will include a summary of 
findings, participant-specific case review, recommendations on any performance 
and/or shortcomings and request for corrective action, when necessary. When 
corrective action is required, the participating site must reply within 45 days of 
receipt of the audit report with their corrective action plan. 
11. 
STATISTICAL CONSIDERATIONS 
11.1 
Endpoints 
The primary endpoint is radiographic progression-free survival (rPFS) defined as the time 
from randomization to minimum of radiographic progression or death, whichever occurs 
first. 


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Secondary endpoints include post-therapy changes in PSA, objective response rate (ORR) 
per RECIST criteria, PSA progression-free survival (PSA PFS), and toxicity. 
11.2 
Sample Size 
This is a randomized phase II trial in which 80 patients will be randomized with equal 
probability to one of two possible treatment regimens: abiraterone acetate\prednisone 
(AA) or AA plus cabazitaxel (AA+C). The randomization will be stratified by Halabi 
nomogram7 based on low (defined as ( 166.6 points in the nomogram) or high risk (>166.6 
total points). 
Based on Ryan et al. the median time to radiographic progression free survival (rPFS) is 
16.5 months. This trial is non-comparative. Forty (40) patients will be enrolled in each arm. 
With an accrual rate of 40 patients/arm over 24-month accrual period, and assuming that 
rPFS follows an exponential distribution, based on 5,000 simulations the average width of a 
two-sided 95% confidence interval for the median rPFS is 16. 
In addition, this trial will estimate the rPFS in patients who are RB negative and treated 
with either AA or AA+C. It is expected that 60% (48) patients will be RB negative and 40% 
(32 patients) will be RB positive. The radiographic PFS distribution by RB status and 
treatment arm will not be estimated with high precision. Nevertheless, the data from this 
study will be valuable for testing feasibility as well as providing pilot data for use in 
planning a larger randomized phase II/III trial. 
Dr. Susan Halabi from Duke University will perform statistical analysis of this trial. Data will 
be de-identified from all sites prior to sending to Dr. Halabi for analysis. 
11.3 
Toxicity Monitoring 
While the combination of AA + C has been safely administered in patients that had prior 
Docetaxel therapy, it is expected that this will also be well tolerated in the pre- 
chemotherapy population. However since it has not been used in the pre-chemotherapy 
population, close toxicity monitoring will occur. An unacceptable toxicity will be defined as 
death or grade 4 febrile neutropenia that is treatment related (probably or definitely 
related to treatment). If at any time during the accrual the observed proportion of 
unacceptable toxicity exceeds 15% by at least one standard error accrual to the trial will be 
immediately suspended and the trial re-evaluated. 
11.4 
Data Analysis 
The trial is non-comparative and the analysis will be performed within each arm. The 
Kaplan-Meier product-limit estimator will be used to estimate rPFS, overall survival, and 
PFS distributions. In addition, the proportion of patients who are RB positive or RB 
negative with exact 95% confidence interval (CI) based on the binomial distribution will be 
computed. RB status will be performed at centralized laboratory at Thomas Jefferson 
University and RB immunohistochemistry status\genomic profile will be performed as 
previously described by Sharma et al.1 
The rPFS distribution will be estimated in subgroups of patients who are RB positive or RB 
negative treated with either AA or AA+C. The rPFS distribution within each arm and RB 
status will not be estimated with high precision. Nevertheless, the data from this study will 


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be valuable for testing feasibility as well as providing pilot data for use in planning a larger 
phase 11\III trial. 
Furthermore, post therapy changes in PSA (50%) and response rates using the RECIST 
criteria (complete+ partial) with exact 95% Cls based on the binomial distribution will be 
computed. Exploratory analysis will be performed to correlate the RB status with PFS and 
other clinical outcomes. 
12. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS 
12.1 
Roles and Responsibilities 
12.1.1 lead Site/Sponsor Principal Investigator 
The Sponsor Principal Investigator at the lead site is responsible for performing the 
following tasks: 
• 
 Responsibility for the overall conduct of the study at all participating sites and for 
monitoring the progress of the study 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 
• 
Reviewing data from all participating sites 
12.1.2 PCCTC 
The PCCTC is responsible for performing the following tasks: 
• 
 Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals and 
required regulatory documents from each site. 
• 
Managing subject registration 
• 
Developing and maintaining Clinical Data Management documents and procedures 
• 
CRF development, setup of study database, and subsequent design changes 
• 
Participating in review of content of the CRF against the protocol requirements 
• 
EDC system administration (user/site accounts setup, maintenance and revocation) 
• 
Data review, cleaning, query management and resolution 
• 
 Establishing procedures for documentation, reporting and submitting of AE's and 
SAE's to the PCCTC. 
• 
Reviewing Serious Adverse Events (SAEs) 
• 
Training participating sites on EDC 
• 
Collecting and compiling data from each participating site 
• 
Data reviewing from all participating sites 
• 
 Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites. 
12.1.3 Participating Sites 
Participating sites are responsible for performing the following tasks: 
• 
 Following the protocol as written, the guidelines of Good Clinical Practice (GCP), and 
applicable Standard Operating Procedures (SOPs).Registering all patients with the 
PCCTC by submitting the eligibility checklist, supporting source documentation, and 
signed informed consent promptly 
• 
 Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol 
• 
 Maintaining regulatory binders on site and providing copies of all required 
documents to the PCCTC 
• 
Collecting and submitting data according to the schedule specified by the protocol 


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• 
Responding to queries in a timely manner 
12.2 
Ethical Considerations 
This study will be conducted in compliance with the protocol, GCP guidelines established by the 
International Conference on Harmonisation, and the ethical standards set forth in the Declaration 
of Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 
12.3 
Regulatory Documentation 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol 
document and each participating site will utilize that document. 
The following documents must be provided to the PCCTC before the participating site can be 
initiated and begin enrolling participants: 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
• 
Participating Site IRB membership list 
• 
Participating Site IRB's Federal Wide Assurance number and OHRP Registration number 
• 
Curriculum vitae and medical licenses for each investigator and consenting professional 
• 
Curriculum vitae for each lab director 
• 
 Consenting Professionals Lists (consenting professionals at each participating site 
that may obtain informed consent and care for the participants according to good 
clinical practice and protocol guidelines) 
• 
 Documentation of Human Subject Research Certification training for investigators and 
key staff members at the participating site 
• 
Documentation of Good Clinical Practice (GCP) training for the Pl and co-Pl at the 
participating site 
• 
Participating site laboratory certifications and normals 
Upon receipt of the required documents, the PCCTC will submit a participating site activation 
request to MSKCC. Once approved, MSKCC will formally contact the PCCTC and grant the site 
permission to proceed with enrollment. 
12.4 
Protocol Amendments 
Before starting the study, the protocol must be approved by each institution's IRB or Independent 
Ethics Committee (IEC). Each change to the protocol document must be organized and 
documented by the PCCTC, reviewed and approved by Sanofi and approved by the MSKCC 
IRB/PB. Protocol amendments that affect MSKCC only (e.g. change in MSKCC Co-Investigator, 
MSKCC translation, etc.) do not require IRB review at the participating site(s). All other protocol 
amendments will be immediately distributed to each participating site upon receipt of MSKCC 
IRB/PB approval. 
Each participating site must obtain approval for all non expedited amendments from their IRB 
within 90 calendar days of MSKCC IRB/PB approval. If the amendment is the result of a safety 
issue or makes eligibility criteria more restrictive, sites will not be permitted to continuing 
enrolling new participants until the participating site IRB approval of the revised protocol 


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document is granted and submitted to the PCCTC, who  will in turn submit the approval 
documentation to MSKCC. 
The following documents must be provided to the PCCTC for each amendment within the stated 
timelines: 
• 
Participating Site IRB approval 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
The PCCTC is responsible for submitting all participating site local IRB approvals and/or 
acknowledgments to MSKCC upon receipt. 


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12.5 
Additional IRB Correspondences 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site's IRB and the most 
current approved version of the informed consent form should be submitted to PCCTC 
within 7 days of expiration. Failure to submit the re-approval in the stated timeline will 
result in suspension of new participant enrollment. The PCCTC is responsible for submitting 
all participating site local IRB approvals and/or acknowledgments to MSKCC upon receipt. 
 Deviations 
A protocol deviation on this study is defined as any incident involving non-adherence to an 
IRB approved protocol. Deviations typically do not have a significant effect on the rights, 
safety, or welfare of research participants or on the integrity of the resultant data. 
Deviations that represent unanticipated problems involving risks to participants or others, 
or serious adverse events should be reported according to sections 8.5.1 and 8.7 of the 
protocol. 
Deviations that do not adversely affect the rights and/or welfare of the participant or the 
scientific validity of the study and are related to protocol scheduling changes outside of the 
allowed window due to a holiday (e.g., New Year's, Thanksgiving, etc.) and/or inclement 
weather or other natural event do not require reporting to the MSKCC IRB/PB. However, 
they must be clearly documented in the patient's medical record. 
Prospective Deviations 
Deviations to the research protocol that involve an informed consent procedure change 
and/or treatment/pharmacy alterations that are not allowed by the protocol require 
prospective approval from the MSKCC IRB/PB prior to the change being carried out. 
Participating sites should contact the PCCTC who will in turn seek approval from the MSK 
IRB/PB. Deviations to the research protocol that involve patient eligibility  will not be 
permitted. 
Retrospective Deviations 
Deviations that include a change or departure from the research protocol without prior 
approval from the MSKCC IRB/PB are considered retrospective deviations. Retrospective 
deviations should be reported to the PCCTC as soon as possible, who will in turn report the 
deviation to the MSKCC IRB/PB as per MSKCC guidelines. 
Participating Site !RB Reporting 
Participating sites should report all deviations to their institution's IRB per local guidelines. 
Approvals/acknowledgments from the participating site IRB for protocol deviations should 
be submitted to the PCCTC upon receipt. The PCCTC is responsible for submitting all 
participating site local IRB approvals and/or acknowledgments to MSKCC upon receipt. 
Other correspondence 
Participating sites should submit other correspondence to their institution's IRB according 
to local guidelines, and submit copies of that correspondence to the PCCTC. The PCCTC is 
responsible for submitting all participating site local IRB correspondences to MSKCC upon 
receipt 


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12.6 
Document Maintenance 
The MSKCC PI and participating site PI will maintain adequate and accurate records to fully 
document protocol implementation and allow data to be subsequently verified. 
The participating sites will ensure that all regulatory documents and participating site IRB 
correspondence are maintained in an on-site regulatory binder and sent to the PCCTC as 
outlined within the protocol. The on-site regulatory binder will be reviewed by the 
designated study monitor at monitoring visits. A regulatory binder for each participating 
site will also be maintained at the PCCTC; this binder may be paper or electronic. 
After study closure, the participating sites must maintain all source documents, study 
related documents and eCRFs for 7 years. 
12.7 
Written Informed Consent 
Before obtaining consent, members of the study team will review the rationale for the 
treatment program with the patient. The discussion will review the alternatives available 
(including hormonal therapy, chemotherapy, or supportive care as appropriate), the 
potential benefits of this program, the risks and the probability of their occurrence, and the 
procedures to minimize these risks. Should an AE occur, the provisions available to ensure 
medical intervention will also be reviewed. Why the risks are reasonable in relation to the 
anticipated benefits, incentives, or costs that will or may be incurred as a result of 
participating in the study, as well as the efforts to maintain confidentiality, will also be 
discussed with the patient. 
Patients will be required to sign and date a statement of informed consent that meets the 
requirements of the Code of Federal Regulations (Federal Register Vol. 46, No. 17, January 
27, 1981, part 50) and the IRB. The medical record will include a statement that written 
informed consent was obtained (and document the date that it was obtained) before the 
patient is enrolled in the study. The original signed document will become part of the 
patient's medical record, a copy will be forwarded to the lead site/sponsor pursuant to 
sponsor registration and to the PCCTC and a copy will be sent home with each patient. 
The consent form will include the following: 
• 
the nature and objectives, potential toxicities, and benefits of the intended study 
• 
the length of therapy and likely follow-up required 
• 
alternatives to the proposed therapy (including available standard and investigational 
therapies) 
• 
the name of the investigator(s) responsible for the protocol 
• 
the right of the patient to accept or refuse treatment and to withdraw from participation 
in this study 
Text regarding the PCCTC should be added to all institutional informed consent 
documents and sections in the research authorization/HIPAA forms (e.g., "Prostate 
Cancer Clinical Trials Consortium") 


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12.8 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. After this discussion, they 
will be asked to sign a Notice of Privacy Practice research authorization/HIPAA form. The 
original signed documents will become part of the patient's medical records, and each 
patient will receive a copy of the signed documents. The use and disclosure of protected 
health information will be limited to the individuals described in the research authorization 
form. The research authorization form must be completed by the principal investigator and 
approved by the IRB. 
12.9 
Terminating or Modifying the Study 
AE and laboratory data from this trial will be assessed by the lead site or the sponsor's 
medical monitor on an ongoing basis. SAEs will be reviewed as they are reported to the lead 
site/sponsor and the PCCTC, and the medical monitor will make an assessment regarding 
the safety of continuing or modifying the study. This assessment will be shared with the 
investigators either in writing or as part of a teleconference. Should the assessment of 
either the lead site/sponsor or the principal investigator be that the study should be 
terminated, the study will be closed to further accrual. Patients who are receiving 
cabazitaxel or abiraterone acetate will be assessed individually by the investigator to see if 
it is in the patients' best interest to continue, which might be the case for a patient that is 
responding to the intervention. Follow-up safety assessments will be performed for all 
patients who are terminated from the study prematurely. 
12.10 Noncompliance 
If a participating site is noncompliant with the protocol document, accrual privileges may be 
suspended and/or contract payments may be withheld, until the outstanding issues have been 
resolved. 
13. 
REFERENCES 
1.  Sharma A, Yeow WS, Ertel A, et al. The retinoblastoma tumor suppressor controls androgen 
signaling and human prostate cancer progression.] Clin Invest. 2010;120(12):4478-4492. doi: 
10.1172/JCI44239; 10.1172/JCI44239. 
2. Bosco EE, Wang Y, Xu H, et al. The retinoblastoma tumor suppressor modifies the therapeutic 
response of breast cancer.] Clin Invest. 2007;117(1):218-228. doi: 10.1172/JCI28803. 
3. Sharma A, Comstock CE, Knudsen ES, et al. Retinoblastoma tumor suppressor status is a critical 
determinant of therapeutic response in prostate cancer cells. Cancer Res. 2007;67(13):6192- 
6203. doi: 10.1158/0008-5472.CAN-06-4424. 
4. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic 
prostate cancer. N Engl J Med. 2011;364(21):1995-2005. doi: 10.1056/NEJMoa1014618. 
5.  Ryan CJ, Smith MR, deBono et al. Abiraterone in metastatic prostate cancer without previous 
chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. doi: 10.1056/NEJMoa1209096. Epub 
2012 Dec 10. 
6. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for 
metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A 


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Page 66 
randomised open-label trial. Lancet. 2010;376(9747):1147-1154. doi: 10.1016/S0140- 
6736(10)61389-X. 
7.  Halabi S, Lin, C, Kelly, W, et al. Updated prognostic model for predicting overall survival in first- 
line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin 
Oncol. 2014; 32:671-677. 
7a. Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with 
hormone-refractory metastatic prostate cancer. J Clin One. 2013; 21:1232-1237. 
8. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 
2009;59(4):225-249. doi: 10.3322/caac.20006. 
9. Lytton B. Prostate cancer: A brief history and the discovery of hormonal ablation treatment.] 
Ural. 2001;165(6  Pt 1):1859-1862. 
10. Sowery RD, So AI, Gleave ME. Therapeutic options in advanced prostate cancer: Present and 
future. Curr Ural Rep. 2007;8(1):53-59. 
11.  Hugh J, Hanson J, Cheang MC, et al. Breast cancer subtypes and response to docetaxel in node- 
positive breast cancer: Use of an immunohistochemical definition in the BCIRG 001 trial.] Clin 
Oneal. 2009;27(8):1168-1176. doi: 10.1200/JCO.2008.18.1024. 
12. Kim C, Paik S. Gene-expression-based prognostic assays for breast cancer. Nat Rev Clin Oneal. 
2010;7(6):340-347. doi: 10.1038/nrclinonc.2010.61. 
13.  Hewish M, Lord CJ, Martin SA, Cunningham D, Ashworth A. Mismatch repair deficient colorectal 
cancer in the era of personalized treatment. Nat Rev Clin Oneal. 2010;7(4):197-208. doi: 
10.1038/nrclinonc.2010.18. 
14. Peppercorn J, Perou CM, Carey LA. Molecular subtypes in breast cancer evaluation and 
management: Divide and conquer. Cancer Invest. 2008;26(1):1-10. doi: 
10.1080/07357900701784238. 
15. Knudsen ES, Knudsen KE. Tailoring to RB: Tumour suppressor status and therapeutic response. 
Nat Rev Cancer. 2008;8(9):714-724. doi: 10.1038/nrc2401. 
16. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. 
Nat Rev Cancer. 2008;8(9):671-682. doi: 10.1038/nrc2399. 
17. Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate 
cancer. Cancer Cell. 2010;18(1):11-22. doi: 10.1016/j.ccr.2010.05.026. 
18. Sun H, Wang Y, Chinnam M, et al. E2f binding-deficient Rb1 protein suppresses prostate tumor 
progression in vivo. Proc Natl Acad Sci US A. 2011;108(2):704-709. doi: 
10.1073/pnas.1015027108. 
19.  Macleod KF. The RB tumor suppressor: A gatekeeper to hormone independence in prostate 
cancer? J Clin Invest. 2010;120(12):4179-4182. doi: 10.1172/JCI45406; 10.1172/JCI45406. 
20. Ertel A, Dean JL, Rui H, et al. RB-pathway disruption in breast cancer: Differential association 
with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle. 
2010;9(20):4153-4163. 
21.  Knudsen KE, Booth D, Naderi S, et al. RB-dependent S-phase response to DNA damage. Mo/ Cell 
Biol. 2000;20(20):7751-7763. 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
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22.  Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus 
prednisone for advanced prostate cancer. N Engl] Med. 2004;351(15):1502-1512. doi: 
10.1056/NEJMoa040720. 
23.  http: //www.jevtana.com/hcp /dosing/preparation-administration.aspx. Updated 2011. 
Accessed October /27, 2011. 
24.  http://www.accessdata.fda.gov/drugsatfda docs/label/2010/201023lbl.pdf. Updated 2010. 
Accessed October /27, 2011. 
25. http://www.accessdata.fda.gov/drugsatfda  docs /label/2011/2 02379lbl.pdf. Updated 2011. 
Accessed October 27, 2011. 
26.  Scher HI, Halabi S, Tannock 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.] Clin Oneal. 2008;26(7):1148-1159. doi: 
10.1200/JCO.2007.12.4487. 


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APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
I 
  Karnofsky Performance Scale 
Grade 
Description 
I 
% 
Description 
Normal, no complaints, no evidence of 
disease 
0 
Normal activity. Fully active, able to 
continue all pre-disease performance 
without restriction. 
100 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity but 
80 
Normal activity with effort, some signs or 
symptoms of disease 
1 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
2 
In bed < 50% of the time. Ambulatory and 
capable of all self-care but unable to carry 
out any work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance but is able 
to care for most needs 
so 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time. Capable of only 
limited self-care, confined to bed or chair 
> 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization indicated. 
Death not imminent. 
4 
100% bedridden. Completely disabled, 
cannot carry on any self-care, totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 


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APPENDIX B: MEDICATIONS WITH THE POTENTIAL FOR DRUG-DRUG INTERACTIONS 
CABAZITAZEL 
No formal clinical drug-drug interaction trials have been conducted with cabazitaxel. 
Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of 
cabazitaxel. 
Drugs That May Increase Cabazitaxel Plasma Concentrations 
CYP3A4 Inhibitors: Cabazitaxel is primarily metabolized through CYP3A. Though no formal drug 
interaction trials have been conducted for cabazitaxel, concomitant administration of strong CYP3A 
inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) is expected to increase concentrations 
of cabazitaxel. Therefore, co-administration with strong CYP3A inhibitors should be avoided. 
Caution should be exercised with concomitant use of moderate CYP3A inhibitors. 
Drugs That May Decrease Cabazitaxel Plasma Concentrations 
CYP3A4 Inducers: Though no formal drug interaction trials have been conducted for cabazitaxel, 
the concomitant administration of strong CYP3A inducers (e.g., phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentin, phenobarbital) is expected to decrease cabazitaxel concentrations. 
Therefore, co-administration with strong CYP3A inducers should be avoided. In addition, patients 
should also refrain from taking St. John's Wort. 
ABIRATERONE 
Based on in vitro data, abiraterone is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors 
(e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, 
ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been 
evaluated, in vivo. It is recommended to avoid or use with caution, strong inhibitors and inducers of 
CYP3A4 during abiraterone treatment 


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APPENDIX C: LABORATORY MANUAL\CORRELATIVE STUDIES 
Please see the Laboratory & Correlative Studies Manual 


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APPENDIX D: STANDARD OPERATING PROCEDURES FOR ULTRASOUND\CT-GUIDED 
BIOPSY OF METASTATIC PROSTATE CANCER LESION 
Please see the Laboratory & Correlative Studies Manual 


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APPENDIX E: LISTING OF EXPECTED/UNEXPECTED ADVERSE EVENTS 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for Cabazitaxel and 
Abiraterone. 
The Comprehensive Adverse Event and Potential Risks (CAEPR) list provides a single, complete list 
of reported and potential adverse events associated with an agent using a uniform presentation of 
events by body system. In addition to the comprehensive list, a subset, the Agent Specific Adverse 
Event List (ASAEL), appears in a separate column. The ASAEL contains events that are considered 
expected for expedited reporting purposes only. Refer to the NCI/CTEP Guidelines: Adverse Event 
Reporting Requirements available athttp://ctep.cancer.gov/reporting/adeers.html for further 
clarification. 
Adverse Events in .::5% of patients receiving cabazitaxel plus prednisone 
Cabazitaxel plus prednisone 
N=371 
Adverse Reaction 
All Grades 
% 
Grades 3-4 
% 
Blood and lymph 
Neutropenia 
Febrile neutropenia 
Anemia 
Leukopenia 
Thrombocytopenia 
94 
7 
98 
96 
48 
82 
7 
11 
69 
4 
Cardiac 
Arrhythmia 
5 
1 
GI Disorders 
Diarrhea 
Nausea 
Vomiting 
Constipation 
Abdominal pain 
Dyspepsia 
47 
34 
22 
20 
17 
10 
6 
2 
2 
1 
2 
0 
General 
Fatigue 
Asthenia 
Pyrexia 
Peripheral edema 
Mucosal inflammation 
Pain 
37 
20 
12 
9 
6 
5 
5 
5 
1 
<1 
<1 
1 
Infections 
Urinary tract infection 
8 
2 
Weight decreased 
9 
0 
Metabolism and nutrition 


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Anorexia 
Dehydration 
16 
5 
<1 
2 
Musculoskeletal 
Back pain 
Arthralgia 
Muscle spasms 
16 
11 
7 
4 
1 
0 
Nervous system 
Peripheral neuropathy 
Dysgeusia 
Dizziness 
Headache 
13 
11 
8 
8 
<1 
0 
0 
0 
Renal and Urinary 
Hematuria 
Dysuria 
17 
7 
2 
0 
Respiratory 
Dyspnea 
Cough 
12 
11 
1 
0 
Skin 
Alopecia 
10 
0 
Vascular 
Hypotension 
5 
<1 


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Adverse reactions due to abiraterone acetate 
Abiraterone with 
Prednisone 
. (N=791) 
Placebo with 
Prednisone (N=394) 
All 
I Grade 3-1All 
IGrade 3-4 
Grades1 
 4 
Grades 
Adverse reaction 
% 
1% 
1% 
1% 
Musculoskeletal and connective tissue disorders 
Joint swelling/ discomfort2 
29.5 
4.2 
23.4 
4.1 
Muscle discomfort3 
1 26.2 
3.0 
23.1 
2.3 
General disorders 
Edema4 
26.7 
1.9 
18.3 
0.8 
Vascular disorders 
Hot flush 
19.0 
0.3 
16.8 
0.3 
Hypertension 
1 8.5 
1.3 
6.9 
0.3 
Gastrointestinal disorders 
Diarrhea 
17.6 
0.6 
13.5 
1.3 
Dyspepsia 
1 6.1 
0 
3.3 
0 
Infections and infestations 
Urinary tract infection 
11.5 
2.1 
7.1 
0.5 
Upper respiratory tract 
infection 
5.4 
0 
2.5 
0 
Respiratory, thoracic and mediastinal disorders 
Cough 
10.6 
0 
7.6 
0 
Renal and urinary disorders 
Urinary frequency 
7.2 
0.3 
5.1 
0.3 
Nocturia 
1 6.2 
0 
4.1 
0 
Cardiac disorders 
Arrhythmias 
7.2 
1.1 
4.6 
1.0 
Chest pain or chest 
discomfort6 
3.8 
0.5 
2.8 
0 
Cardiac failure7 
2.3 
1.9 
1.0 
0.3 
1 Adverse events graded according to CTCAE version 4.0 
2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness, 
3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, 
and Musculoskeletal stiffness 
4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalised edema 
5 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, 
Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block 
complete, Conduction disorder, and Bradyarrhythmia. 
6 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or 
ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% 
respectively). 
7 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, 
Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 75 
APPENDIX F: GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
AdEERS 
Adverse Event Expedited Reporting System 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AR 
androgen receptor 
ASAEL 
Agent Specific Adverse Event List 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
Bid 
bis in die (twice a day) 
BLQ 
below limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
BSA 
Body Surface Area 
BUN 
blood urea nitrogen 
C 
Celsius 
cDNA 
Circulating DNA 
Ca++ 
calcium 
CAEPR 
Comprehensive Adverse Event and Potential Risks 
CBC 
complete blood count 
CDUS 
Clinical Data Update System 
CFR 
Code of Federal Regulations 
Cl 
confidence interval 
Cl- 
chloride 
Cler 
creatinine clearance 
Cm 
centimeter 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRPC 
castration resistant prostate cancer 
CT 
computerized tomography 
CTC 
circulating tumor cell 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 76 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
coefficient of variation 
CYP 
cytochrome p-450 
dL 
deciliter 
DHEA 
dehydroepiandrosterone 
DLT 
dose-limiting toxicity 
DNA 
Deoxyribo Nucleic Acid 
DSM 
data and safety monitoring 
ECOG 
Eastern Cooperative Oncology Group 
EKG 
electrocardiogram 
F 
bioavailability 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GFR 
glomerular filtration rate 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunochemical 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
LC 
liquid chromatography 
LDH 
lactate dehydrogenase 
Ln 
natural logarithm 
LOCF 
last observation carried forward 
LOI 
letter of intent 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
MRI 
magnetic resonance imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MS 
mass spectrometry 
MTD 
maximum tolerated dose 
N 
number of subjects or observations 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 77 
NA 
not applicable 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
PCCTC 
Prostate Cancer Clinical Trials Consortium 
PCRP 
Department of Defense Prostate Cancer Research Program 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
Pl 
principal investigator 
PK 
pharmacokinetics 
PCa 
Prostate Cancer 
PO 
per os (by mouth) 
POD 
Progression of Disease 
PR 
partial response 
PSA 
prostate-specific antigen 
PSA-DT 
prostate-specific antigen doubling time 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Qd 
quaque die (every day) 
QOL 
quality of life 
RBC 
red blood cell 
RB+ 
Retinoblastoma tumor suppressor+ 
RB- 
Retinoblastoma tumor suppressor - 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP 
radical prostatectomy 
RSA 
Research Study Assistant 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SD 
stable disease 
SOP 
Standard Operating Procedures 
T 
temperature 
tl/2 
terminal half-life 
T 
time 
Tid 
ter in die (3 times a day) 
TX 
treatment 
ULN 
upper limit of normal 
Vss 
volume of distribution at steady-state 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 78 
WBC 
WHO 
white blood cell 
World Health Organization 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 79 
APPENDIX G. PILL DIARY 
Please see the attached patient pill diary. 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 80 
APPENDIX H: STANDARD OPERATING PROCEDURE FOR SHIPMENT OF CLINICAL 
SAMPLES 
Please see the Laboratory & Correlative Studies Manual 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 81 
APPENDIX I: 1 ST SAE REPORT 
Sanofi ISS Serious Adverse Event Cover Page 
Fax: 
To: 
I 
I 
I 
Investigator Sponsored Studies (ISS) SAE Report 
US Pharmacovigilance 
VisionTracker # / ClubNet#: 
CABAZL06066 
Study Title: 
An Exploratory Randomized Phase II Multicenter Trial of 
Abiraterone Acetate with or without Cabazitaxel in 
Treatment of Metastatic Castration Resistant Prostate Cancer 
PI Name: 
Susan Slovin, MD 
Causality: 
All serious, related adverse events will be reported and documented on MedWatch Form 
FDA 3500A 
(http://www.fda.gov/downloads /AboutFDA/ReportsManualsForms/Forms/UCM163919. 
pd_f) and forwarded directly to sanofi-aventis Pharmaceuticals. This includes serious, 
related, labeled (expected) and serious, related, unlabeled (unexpected) adverse 
experiences. 
For Comparator Drugs / Secondary Suspects (Concomitant 
Medications), 
all 
serious 
adverse 
experiences 
will 
be 
forwarded to the product manufacturer. 
Check one: 
I
 Unrelated:  The adverse event is clearly NOT related. 
Unlikely to be related: 
The adverse event is doubtfully 
related. 
I
Possibly related: The adverse event may be related. 
I
Probably related: The adverse event is likely related. 
I
 Definitely related:  The adverse event is clearly related. 
Fax: 908-203-7783 or Email to: USPVmailbox@sanofi.com 
Date: 
Pages: 
From: 
Phone: 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 82 
APPENDIX J: PCCTC SERIOUS ADVERSE EVENT REPORT FORM 
Please see the supplemental PCCTC Serious Adverse Event Form 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 83 
APPENDIX K: PCCTC BONESCAN ASSESSMENT TOOL 
Use the attached Appendix Bone Scan PCCTC Tool. 


MSK IRB#: 14-046 A(12), Approval Date: 31-0ct-2022 
Cabazitaxel and Abiraterone Acetate 
MSKCC 
PCCTC LOI: c12-108 
IRB#: 14-046 A(B) 
Page 84 
APPENDIX L: HALABI NOMOGRAM RISK 
Use the following link for the Halabi Nomogram and see instructions below for completion: 
https://www.cancer.duke.edu/Nomogram / firstlinechemotherapy.html 
1. Accept terms of the Disclaimer 
2. For Display Output, select "Yes" 
3. For Risk Group Classification, select "2 Groups" 
4. Complete the remaining questions as according to the patient's source documentation 
5. DO NOT provide patient ID. 
6. Click "Validate" once complete 
7. Click "PDF Results File". 
8. Print the results and write in the patient's MRN as the patient ID for submission to the 
patient's EMR, for source documentation