Phase II Study of Abiraterone Acetate and Prednisone in Combination With Cabazitaxel, Compared to Cabazitaxel Alone, in Patients With Metastatic Castrate Resistant Prostate Cancer.
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: University of Colorado, Denver

 
1
Local Protocol #: 
 13-1489 
 
 
 
 
 
 
 
Version: 11.2, June 28, 2016  
 
 
 
TITLE: Phase II Study of Abiraterone Acetate and Prednisone in Combination with Cabazitaxel Compared to 
Cabazitaxel Alone, in Patients with Metastatic Castrate Resistant Prostate Cancer. 
 
Coordinating Center:  
 
University of Colorado Cancer Center 
 
Sponsor/Principal Investigator: 
Elaine Lam, MD 
University of Colorado Denver, Division of Medical Oncology 
12801 East 17th Avenue, MS 8117 
Aurora, CO 80045 
Phone: 720-848-0273 
Fax: 303-724-3889 
 
Elaine.lam@ucdenver.edu 
 
Co-Investigators: 
Elizabeth Kessler, MD 
 
Thomas W. Flaig, MD 
 
Kathryn Breaker, APN 
 
Mali Wold, APN 
 
Statistician: 
 
 
  Dexiang Gao, PhD 
 
 
 
IND information: 
FDA IND exemption – Dated: 1.18.2013 

 
2
Protocol Summary 
 
 
 
Phase II Study of Abiraterone Acetate and Prednisone in Combination with Cabazitaxel, 
Compared to Cabazitaxel Alone,  in Patients with Metastatic Castration-Resistant Prostate Cancer. 
Primary Objective 
To assess the anti-cancer efficacy of abiraterone acetate and cabazitaxel , compared 
with cabazitaxel alone, in patients with mCRPC, as determined by progression-free 
survival at 3 months. 
Secondary 
Objectives 
 
To assess the anti-cancer efficacy of abiraterone acetate and cabazitaxel, compared 
with cabazitaxel alone, in patients with mCRPC, as determined by PSA response, 
maximum PSA decline during study treatment, time to PSA and radiographic 
progression, radiographic objective response, median progression-free survival, 
and overall survival at two years. 
 
To assess ongoing safety and tolerability of the combination of abiraterone acetate 
and cabazitaxel. 
Study Population  
Metastatic castrate-resistant prostate cancer. 
Prior treatment with both docetaxel and abiraterone acetate. 
STUDY DESIGN  
Arm A: Cabazitaxel monotherapy 
1. Patients will receive cabazitaxel 25 mg/m2 intravenously every 3 weeks, until radiographic disease 
progression per RECIST 1.1, unacceptable toxicity, or patient withdrawal. 
2. Patients will receive prednisone 5mg orally BID. 
3. Patients will continue on LHRH agonist or antagonist, unless surgically castrate. 
4. Patients will receive pegfilgrastim or filgrastim support with cabazitaxel dosing. 
Arm B: Cabazitaxel + Abiraterone Acetate 
1. Patients will receive cabazitaxel 25 mg/m2 intravenously every 3 weeks, in combination with oral 
abiraterone acetate 1000 mg daily, until radiographic disease progression per RECIST 1.1, 
unacceptable toxicity, or patient withdrawal. 
2. Patients will receive prednisone 5mg orally BID. 
3. Patients will continue on LHRH agonist or antagonist, unless surgically castrate. 
4. Patients will receive pegfilgrastim or filgrastim support with cabazitaxel dosing. 

 
3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 PSA every 3 weeks (on day 1 of each 21-day cycle). 
2 ECG (electrocardiogram) performed at screening visit and C2D1 visit. 
3 CT chest, abdomen, and pelvis and whole body bone scan will be performed at baseline (within 28 days of C1D1) and every 12 weeks. 
4 Prednisone is given on a continuous daily basis (5mg orally BID) beginning with C1D1. 
5 Pegfilgrastim is given on day 2 of each cycle.  If pegfilgrastim is not covered by patient’s insurance, or not tolerated, then substitution with filgrastim per institutional guidelines will be allowed. 
 
 
 
 
 
 
 
 
 
Table 1: Arm A 
Screen C1D1 C1D2 C2D1 C2D2 C3D1 C3D2 CnD1 CnD2 EOS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Adverse events assessment 
X 
X 
 
X 
 
X 
 
X 
 
X 
Review medication list 
X 
X 
 
X 
 
X 
 
X 
 
X 
Physical exam and history 
X 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
Performance Status 
X 
X 
 
X 
 
X 
 
X 
 
X 
CBC, CMP 
X 
X 
 
X 
 
X 
 
X 
 
X 
PSA1 
 
X 
 
X 
 
X 
 
X 
 
X 
Testosterone, HgbA1C    
X 
 
 
 
 
 
 
 
 
X 
Electrocardiogram2 
X 
 
 
X 
 
 
 
 
 
 
CT 3 
X 
 
 
 
 
 
 
X 
 
 
Nuclear Bone scan 3 
X 
 
 
 
 
 
 
X 
 
 
Prednisone4 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cabazitaxel infusion 
 
X 
 
X 
 
X 
 
X 
 
 
Neulasta injection5 
 
 
X 
 
X 
 
X 
 
X 
 

 
4
 
 
 
 
 
1 PSA every 3 weeks (on day 1 of each 21-day cycle).  
2 ECG (electrocardiogram) performed at screening visit and C2D1 visit. 
3 CT chest, abdomen, and pelvis and whole body bone scan will be performed at baseline (within 28 days of C1D1) and every 12 weeks.  
4 Abiraterone acetate and prednisone are given on a continuous daily basis.  Prednisone and abiraterone acetate will start on C1D1. 
5 Pegfilgrastim is given on day 2 of each cycle. If pegfilgrastim is not covered by patient’s insurance, or not tolerated, then substitution with filgrastim per institutional guidelines will be allowed. 
6 Liverfunction test analysis will be done at least every 2 weeks during first 3 months on abiraterone,  Day 1 and Day 15 of cycles 1-4. 
Table 2: Arm B 
Screen C1D1 C1D2 C1D15 C2D1 C2D2 C2D15 C3D1 C3D2 C3D15 C4D1 C4D2 C4D15 CnD1 CnD2 EOS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
assessment 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Review medication 
list 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Physical exam and 
history 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Vital signs 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
CBC, CMP 
X 
X 
 
X6 
X 
 
X6 
X 
 
X6 
X 
 
X6 
X 
 
X 
PSA1 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
Testosterone, 
HgbA1C    
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Electrocardiogram2 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CT 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Nuclear Bone scan 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Abiraterone 
acetate,4 
Prednisone4   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cabazitaxel infusion 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Neulasta injection5 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 

 
5
 
 
Table of Contents 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ...................................................................................... 10 
1. BACKGROUND AND STUDY RATIONALE ........................................................................................................... 12 
1.1 Prostate Cancer .................................................................................................................................................................... 12 
1.2 Cabazitaxel ............................................................................................................................................................................. 12 
1.2.1 Pegfilgrastim and filgrastim ........................................................................................................................................................ 12 
1.3 Abiraterone acetate ............................................................................................................................................................ 13 
1.3.1 Prednisone .......................................................................................................................................................................................... 13 
1.4 Rationale for Combination of Abiraterone Acetate and Cabazitaxel ................................................................ 14 
1.4.1 Drug Metabolism and Pharmacokinetics ............................................................................................................................... 14 
1.4.2 Overlapping Toxicities ................................................................................................................................................................... 15 
1.4.3 Drug-Drug Interaction Risk Assessment ................................................................................................................................ 15 
1.5 Rationale for Change in Current Study Design .......................................................................................................... 15 
2. STUDY OBJECTIVES .................................................................................................................................................. 16 
2.1 Primary Objectives .............................................................................................................................................................. 16 
2.2 Secondary Objectives ......................................................................................................................................................... 16 
3. STUDY ENDPOINTS ................................................................................................................................................... 16 
3.1 Primary Endpoints .............................................................................................................................................................. 16 
3.2 Secondary Endpoints .......................................................................................................................................................... 16 
4. STUDY DESIGN ........................................................................................................................................................... 17 
4.1 Overview of Study Design ................................................................................................................................................. 17 
4.2 Duration of Study ................................................................................................................................................................. 17 
4.3 Overview of Drug Administration .................................................................................................................................. 17 
4.4 Criteria for Dose Administration ................................................................................................................................... 18 
4.4.1 Study Drug Administration .......................................................................................................................................................... 18 
4.4.2 Clinical Benefit .................................................................................................................................................................................. 19 
4.5 Dose Modification Guidelines .......................................................................................................................................... 19 
4.5.1 Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment ..................................................... 19 
4.5.2 Criteria for Dose Modification (Delays, Reductions, and Discontinuations) ........................................................... 19 
4.5.3 Guidelines regarding monitoring of patients while on abiraterone acetate ........................................................... 19 
4.5.4 Dose Adjustments for Hematologic and Non-Hematologic Toxicity: ......................................................................... 20 
5. STUDY POPULATION................................................................................................................................................ 25 
5.1 Inclusion Criteria ................................................................................................................................................................. 25 
5.2 Exclusion Criteria................................................................................................................................................................. 26 
6. STUDY PROCEDURES AND ASSESSMENTS ........................................................................................................ 28 
6.1 Informed Consent ................................................................................................................................................................ 28 
6.2 Study Visits ............................................................................................................................................................................. 28 
6.2.1 Physical Examination ..................................................................................................................................................................... 28 
6.2.2 Schedule of Events Arm A and Arm B ..................................................................................................................................... 28 
7. STUDY ASSESSMENTS .............................................................................................................................................. 29 
7.1 Efficacy Evaluations ............................................................................................................................................................ 29 
7.2 Safety Evaluations ................................................................................................................................................................ 30 
7.2.1 Adverse Events ................................................................................................................................................................................. 30 
7.2.2 Clinical Laboratory Evaluations................................................................................................................................................. 30 
7.2.3 Concomitant Medication and Therapies ................................................................................................................................ 31 
7.2.4 Completion of Study ....................................................................................................................................................................... 32 
7.2.5 Withdrawal of Patients from Study .......................................................................................................................................... 32 

 
6
7.3 Study Compliance ................................................................................................................................................................ 32 
8. INVESTIGATIONAL AGENTS .................................................................................................................................. 32 
8.1 Precautions and Restrictions .......................................................................................................................................... 32 
8.2 Description of Investigational Agents .......................................................................................................................... 33 
8.2.1 Abiraterone acetate ........................................................................................................................................................................ 33 
8.2.2 Cabazitaxel .......................................................................................................................................................................................... 33 
8.2.3 Prednisone .......................................................................................................................................................................................... 33 
8.2.4 Pegfilgrastim ...................................................................................................................................................................................... 33 
8.2.5 Filgrastim ............................................................................................................................................................................................ 33 
8.3 Preparation, Reconstitution, and Dispensation ....................................................................................................... 33 
8.4 Storage, Handling, Accountability .................................................................................................................................. 33 
8.4.1 Cabazitaxel .......................................................................................................................................................................................... 33 
8.4.2 Abiraterone acetate ........................................................................................................................................................................ 34 
8.4.3 Handling and Accountability ....................................................................................................................................................... 34 
9. STUDY CONDUCT ....................................................................................................................................................... 34 
9.1 Arrangements for Recruitment of Patients ................................................................................................................ 34 
9.2 Treatment Group Assignments ....................................................................................................................................... 35 
10. STATISTICAL AND QUANTITATIVE ANALYSES ............................................................................................ 35 
10.1 Statistical Methods ............................................................................................................................................................ 35 
10.1.1 Sample Size ...................................................................................................................................................................................... 35 
10.1.2 Aim Analysis .................................................................................................................................................................................... 36 
10.1.3 Accrual ............................................................................................................................................................................................... 36 
10.2 Safety Population .............................................................................................................................................................. 36 
10.3 PSA Response Evaluable Population .......................................................................................................................... 36 
10.4 Tumor-Response Evaluable Population ................................................................................................................... 36 
11. SAFETY ANALYSIS .................................................................................................................................................. 36 
12. ADVERSE EVENTS ................................................................................................................................................... 37 
12.1 Definitions ........................................................................................................................................................................... 37 
12.2 Management of Adverse Events, Serious Adverse Events and Special Reporting Situations ................ 39 
12.3 Recording of Adverse Events, Serious Adverse Events and Special Reporting Situations ...................... 39 
12.4 Maintenance of Safety Information ............................................................................................................................ 40 
12.5 Reporting Timelines ......................................................................................................................................................... 40 
12.6 Transmission Methods: ................................................................................................................................................... 40 
12.7 Procedures for Reporting Adverse Events (AE), Serious Adverse Events (SAE), Special Reporting 
Situation, and Product Quality Complaints (PQCs) to Janssen Scientific Affairs ................................................. 41 
12.7.1 Serious Adverse Events (SAE), Adverse Events of Special Interest, and Special Reporting Situations .... 41 
12.7.2 Product Quality Complaints ...................................................................................................................................................... 41 
12.7.3 Reconciliation of SAEs ................................................................................................................................................................. 41 
12.8 Reporting of Serious Adverse Events to the FDA ................................................................................................... 41 
12.9 Dissemination of Safety Information from Janssen Scientific Affairs to Principal Investigator .......... 42 
12.10 Monitoring of Adverse Events and Period of Observation .............................................................................. 42 
12.11 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ...................................... 42 
13. ADMINISTRATIVE REQUIREMENTS ................................................................................................................. 42 
13.1 Data Quality Assurance ................................................................................................................................................... 42 
13.2 Study Monitoring ............................................................................................................................................................... 43 
13.3 Ethical Considerations ..................................................................................................................................................... 43 
13.4 Patient Information and Informed Consent ............................................................................................................ 43 
13.5 Patient Confidentiality .................................................................................................................................................... 43 
13.6 Investigator Compliance ................................................................................................................................................. 43 
13.7 On-site Audits ..................................................................................................................................................................... 43 
13.8 Investigator and Site Responsibility for Drug Accountability .......................................................................... 44 

 
7
13.9 Closure of the Study .......................................................................................................................................................... 44 
13.10 Record Retention ............................................................................................................................................................ 44 
14. USE OF INFORMATION .......................................................................................................................................... 44 
15. REFERENCES ............................................................................................................................................................ 45 
16. APPENDICES ............................................................................................................................................................. 47 
16.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status .............................................. 47 
 
 

 
8
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Term 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration versus time curve 
AUC0-48hr 
Area under the plasma concentration versus time curve zero to 48 hours 
AUC0-τ 
Area under the plasma concentration versus time curve zero to next dose 
CBC 
Complete blood count 
CI 
Confidence interval 
CL 
Clearance 
CL/F 
Apparent oral clearance 
Cmax 
Maximum plasma concentration 
CR 
Complete remission or complete response  
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough concentration 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction  
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GLP 
Good Laboratory Practices 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
IC50 
Concentration producing 50% inhibition 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 

 
9
Abbreviation 
Term 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LHRH 
Leutinizing hormone releasing hormone 
mCRPC 
Metastatic castrate-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
PI 
Principal investigator 
PD 
Pharmacodynamic(s)  
PFS 
Progression-free survival 
Pgp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PR 
Partial remission or partial response  
PSA 
Prostate specific antigen 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended  phase 2 dose 
SAE 
Serious adverse event 
SD 
Stable disease 
STD 
Severe Toxic Dosage 
Tmax 
First time to maximum plasma concentration 
ULN 
Upper limit of the normal range 
Vss 
Volume at steady state 
WHO 
World Health Organization 
 
 
 
 
 

 
10
1.    
BACKGROUND AND STUDY RATIONALE 
1.1    
Prostate Cancer 
Prostate cancer is the most common non-cutaneous cancer in men in the United States, and the second 
leading cause of cancer death in US men (1).  As many as three-quarters of prostate cancer patients 
present with localized disease yet a good proportion have recurrent or metastatic disease requiring 
systemic treatment with androgen deprivation therapy (ADT).  This is our most effective form of 
systemic therapy; however, the majority of prostate cancer cases will become resistant to castrate levels 
of testosterone.  We continue to learn that maximum suppression of androgen production or signaling 
may improve response even in castrate-resistant populations.  Patients with castrate-resistant prostate 
cancer may have an overall survival of 12-25 months based on recent trial data (2-5).  Currently, 
patients receive hormonal manipulation early on and are then offered chemotherapy as their disease 
progresses.  In the last few years, we have seen the approval of several new agents for use in the post-
chemotherapy setting.  The present challenge is to evaluate how these drugs may be used in 
combination. 
1.2 
Cabazitaxel 
Cabazitaxel is a novel semi-synthetic taxane which binds tubulin, inhibiting microtubule formation 
and thus cell division(6).  Additionally, taxanes may also influence the androgen receptor by inhibiting 
nuclear translocation and signaling(7, 8).  Cabazitaxel is currently FDA approved for the treatment of 
metastatic castrate-resistant prostatic adenocarcinoma that is refractory to docetaxel chemotherapy(9).  
Taxanes, such as docetaxel, are susceptible to the p-glycoprotein (p-gp) transporter that decreases the 
efficacy of the drug.  However, cabazitaxel is less influenced by p-gp and able to overcome taxane 
resistance as evidenced in a phase III trial of patients that had progressed on previous docetaxel 
therapy.  The TROPIC trial, which led to FDA approval, patients received cabazitaxel 25mg/m2 and 
prednisone or mitoxantrone 12mg/m2 and prednisone.  The study showed a 2.6-month survival 
advantage for patients treated with cabazitaxel.  The hazard ratio (HR) for death was 0.70 (95% CI, 
0.59-0.83; p<0.0001) and other endpoints of progression free survival (PFS) and PSA response (39% 
v 17.8%) were also significantly improved in those receiving cabazitaxel.  Additionally, a tumor 
response rate based on RECIST was reported at 14.4% in the cabazitaxel group as compared to 4.4% 
for those treated with mitoxantrone (9).  The approved dose is 25mg/m2 intravenously every 21 days.  
 
The most commonly reported toxicities associated with the clinical use of cabazitaxel include anemia, 
leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, asthenia, anorexia, peripheral 
neuropathy, hematuria, and back pain as reported in the full prescribing information(10). The above 
toxicities are the most common of all grades, while the most common grade 3/ 4 toxicities mainly 
included the hematologic effects of neutropenia, leukopenia, anemia, and febrile neutropenia.  
Additional grade 3/ 4 toxicities were fatigue and asthenia.  The most common adverse reaction leading 
to drug discontinuation was neutropenia, with 5 patients experiencing related fatal infectious events.  
In fact, the FDA has issued a warning for febrile neutropenia and recommended that patients at high 
risk be prophylactically treated with colony stimulating factors.   
 
1.2.1 
Pegfilgrastim and filgrastim 
Pegfilgrastim and filgrastim are synthetic forms of granulocyte colony stimulating factor administered 
in order to decrease the incidence of infection in patients receiving myelosuppressive anti-cancer 
therapy that carry a significant risk of febrile neutropenia.  Pegfilgrastim is a subcutaneous injection 
commonly given once per cycle, 24-72 hours after chemotherapy infusion.  Filgrastim is given daily 
for 5 days each cycle.  Bone pain and pain in extremity occurred at a higher incidence in pegfilgrastim- 
and filgrastim-treated patients as compared with placebo-treated patients. Uncommon risks of 
pegfilgrastim and filgrastim use include splenic rupture, acute respiratory distress syndrome, allergic 
reactions, or sickle cell crisis.   

 
11
 
1.3 
Abiraterone acetate 
Abiraterone acetate is a selective irreversible oral inhibitor of CYP17 that has shown a survival benefit 
in patients with metastatic castrate-resistant prostate cancer after progression on docetaxel(11).  
Abiraterone acetate is a pro drug that converted to abiraterone in vivo. Abiraterone is an inhibitor of 
17 alpha-hydroxylase/C17, 20-lyase (CYP17), which is expressed in testicular, adrenal, and prostatic 
tumor tissues.  The enzyme is required for androgen synthesis by catalyzing the formation of 
dehydroepiandrosterone (DHEA) and androstenedione, which are precursors of testosterone.  By 
inhibiting the function of the CYP17 enzyme, steroid production downstream is inhibited, and a 
patient’s testosterone level will drop considerably, with approximately ten-fold higher potency for 
CYP 17 than ketoconazole(12).  Ryan et al included 19 patients previously treated with ketoconazole 
in the phase I trial, and 47% of them responded, supporting the strength of the therapy and the 
remaining sensitivity seen in these androgen-dependent pathways(13).  The phase III COU-AA-301 
trial looked at 1195 patients with docetaxel based chemotherapy-refractory metastatic CRPC and 
showed a median overall survival in the abiraterone acetate plus prednisone arm of 14.8 months 
compared to 10.9 months in the placebo with prednisone arm (HR 0.646; p<0.0001) (14).  There was 
a significantly improved PSA response rate of 38% vs. 10% and a delayed PFS of 5.6 vs. 3.6 months.  
The response rate based on RECIST was 14% in comparison to 3% (p<0.001).  The COU-AA-302 
trial evaluated the use of abiraterone acetate prior to chemotherapy (15).  This trial compared the 
clinical benefit of abiraterone acetate and prednisone to a placebo and prednisone in mCRPC patients 
without prior chemotherapy.  Interim analysis over a median follow up time of 27.1 months has shown 
a statistically significant benefit in progression free survival (16.5 vs. 8.2 months, p <0.0001) and in 
overall survival (35.3 vs. 30.1 months, p = 0.0151) (16).  Based on the results of these trials, abiraterone 
acetate (Zytiga®) is indicated in combination with prednisone for the treatment of patients with 
metastatic castration-resistant prostate cancer. 
The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot 
flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.  
Adverse events of special interest throughout all phase of clinical trials were mineralocorticoid excess 
(edema, hypokalemia and hypertension), cardiac adverse reactions and liver toxicities.  These 
symptoms were minimized, though not completely eradicated, with 5mg of prednisone twice daily. 
The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, 
hypertriglyceridemia, 
lymphopenia, 
hypercholesterolemia, 
hyperglycemia, 
elevated 
AST, 
hypophosphatemia, elevated ALT and hypokalemia (17). 
 
1.3.1 
Prednisone 
Prednisone is a synthetic corticosteroid administered orally as replacement therapy in adrenocortical 
deficiency states.  It is used in combination with abiraterone acetate in order to decrease the symptoms 
of mineralocorticoid excess.  Prednisone is also regularly administered with cabazitaxel at a dose of 
10mg daily.  Common side effects of prednisone use include fluid retention, cataracts, increased risk 
of gastritis, Cushing syndrome, insomnia, and increased appetite.  Additionally, steroid use will alter 
glucose metabolism.  The approved dose of prednisone in combination with abiraterone acetate is 5mg 
orally twice daily and has been studied in the phase II and III trials. 
 
 
1.4 
Rationale for Combination of Abiraterone Acetate and Cabazitaxel 
The combination of abiraterone acetate and cabazitaxel offers treatment of castrate resistant prostate 
cancer utilizing both hormone directed therapy and a cytotoxic approach.  Traditionally, agents that 
block production of androgens from the testes have manipulated the androgen axis.  Abiraterone 

 
12
acetate offers blockade of androgen production of all sources of testosterone (testes, adrenals, tumor), 
thus accentuating the anti-proliferative effect on tumor cells.  Both clinical and preclinical data support 
the importance of maximizing the decrease in androgen availability to inhibit disease progression(18). 
The combination of LHRH agonists and abiraterone acetate will decrease testosterone production from 
multiple sources.  In practice, androgen blockade is commonly continued even beyond disease 
progression and once a patient’s disease becomes castrate resistant, additional agents are added to the 
blockade.  Abiraterone acetate has already shown promising efficacy in the pre-chemotherapy 
setting(15).  Additionally, chemotherapy is often used to treat castrate resistant prostate cancer based 
on its different mechanism of action.  The effectiveness of cabazitaxel in the castrate resistant setting 
has been proven, and there clearly exists rationale to continue maximal androgen blockade, thus the 
combination of abiraterone acetate and cabazitaxel is very clinically relevant.  Using the combination 
of cabazitaxel and abiraterone acetate is rational in that each individual agent has shown a survival 
benefit through differing mechanisms, and understanding whether they will result in additive or 
synergistic efficacy is an important clinical question.  
 
 
1.4.1 
Drug Metabolism and Pharmacokinetics 
 
Abiraterone acetate 
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 1,000 
mg dose of abiraterone acetate. At the dose of 1,000 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. No 
major deviation from dose proportionality was observed in the dose range of 250 mg to 1,000 mg. 
However, the exposure was not significantly increased when the dose was doubled from 1,000 to 2,000 
mg (8% increase in the mean AUC). 
Systemic exposure of abiraterone is increased when abiraterone acetate is administered with food. 
Abiraterone Cmax and AUC0-∞ 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 
ZYTIGA 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 ZYTIGA is taken and for at least 
one hour after the dose of ZYTIGA is taken. The tablets should be swallowed whole with water. 
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. 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. 

 
13
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) (17). 
 
Cabazitaxel 
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.  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. 
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 CYP3A4/5) is low. In addition, cabazitaxel did not induce CYP isozymes (-1A, -2C 
and -3A) in vitro.  A drug interaction study in 11 patients with advanced cancers has shown that 
cabazitaxel (25 mg/m2 administered as a single 1-hour infusion) did not modify the plasma levels of 
midazolam, a probe substrate of CYP3A. Therefore, cabazitaxel is not an inhibitor of CYP3A in vivo. 
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 α-, β-, and γ- half-lives of 4 minutes, 2 hours, and 95 hours, respectively 
(20). 
 
1.4.2 
Overlapping Toxicities   
Phase III data on toxicities associated with each of these individual agents have been reported.  
Cabazitaxel associated AEs include significant hematologic toxicities as well as fatigue, neuropathy, 
nausea/vomiting and diarrhea.  These toxicities are generally manageable with supportive care, 
although some treatment related deaths were associated with febrile neutropenia while on treatment 
with cabazitaxel.  Therefore, colony stimulating factor use is also permissible.  The reported AEs of 
abiraterone acetate involve the adreno-corticosteroid axis, consequently, patients experienced 
hypertension, fluid retention and hypokalemia.  Liver function test abnormalities were also observed   

 
14
Potential overlapping toxicities are expected to be limited to GI toxicities or abnormal liver function 
tests.  A review of full safety information will be conducted throughout this trial. 
 
The phase 2 data from this trial was presented at ASCO GU Symposium 2015.  Twenty-seven patients 
were treated in the phase 2 part of the study. Main treatment-emergent adverse events (AE) Grade≥3 
were neutropenia (15 pts; 55%; 1 pt [3.7%] had febrile neutropenia), fatigue (4 pts; 15%) and sepsis 
(3 pts; 11%). A 1-sided exact test was planned to test a null hypothesis of PSA-RR 25%, with a type 
1 error of 0.05. With a sample size of 26, this test would have a power of 83% under the alternative 
hypothesis of PSA-RR 50%. Of 26 patients evaluable for the primary endpoint, 12 achieved a PSA 
response (PSA-RR 46.2%; 95% CI 26.6–66.4%) and therefore the null hypothesis was rejected (22).   
 
1.4.3 
Drug-Drug Interaction Risk Assessment 
 
Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 
drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were 
increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 
1,000 mg daily and prednisone 5 mg twice daily.  Coadministration of abiraterone acetate with 
substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine) should be avoided. If 
alternative treatments cannot be used, exercise caution and consider a dose reduction of the 
concomitant CYP2D6 substrate drug. 
 
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 
substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg 
abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a 
CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA.  Cabazitaxel 
has a narrow therapeutic index and was suggested by the FDA as an example for a possible drug-drug 
interaction with abiraterone acetate at the level of CYP2C8; therefore further testing of this 
combination is warranted. 
 
Moreover, cabazitaxel is primarily metabolized through CYP3A. Co-administration with strong 
CYP3A inhibitors should be avoided and caution should be exercised with concomitant use of 
moderate CYP3A inhibitors.  Abiraterone acetate inhibits CYP17A1 to block androgen production, 
however all CYP450 enzymes contain similar cofactors and thus abiraterone acetate has been found 
to inhibit CYP3A4/5.  In preclinical studies, abiraterone acetate has been found to inhibit CYP3A4 at 
an IC50 ranging from 2.7 to 11µM(19).  Therefore, the combination of these agents may alter plasma 
levels of cabazitaxel.  While significant overlapping toxicity is not anticipated between these two 
agents, the known toxicities of cabazitaxel may be potentiated by this altered metabolism, including 
hematologic toxicities.  Therefore it is imperative that we have a better understanding of the toxicities 
of the combination of these two agents.  Additional details on drug-drug interactions and concomitant 
therapies will be addressed in section 7.3.3.   
 
1.5 
Rationale for Change in Current Study Design 
We originally conceived and designed this trial as a phase I/II clinical trial to explore the maximum 
tolerated dose, safety and efficacy of the combination of abiraterone acetate and cabazitaxel.  Massard 
and colleagues reported the MTD results of the combination with abiraterone acetate and cabazitaxel 
from their Phase I trial recently. The reported MTD doses were the currently approved doses of each 
drug individually, cabazitaxel 25 mg/m2 and abiraterone acetate 1000 mg/day(21).  Daily abiraterone 

 
15
acetate did not affect the clearance of cabazitaxel.  Cabazitaxel did not affect the exposure of 
abiraterone acetate.  In the phase I portion of the trial by Massard and colleagues, ten patients (median 
age 63) were treated in two cohorts with a median of 4 cycles.  Grade 3 or 4 adverse effect of 
neutropenia was seen in 1 of 3 patients in cohort 1 and 1 of 7 patients in cohort 2.  The phase II single 
arm study of this combination is ongoing (NCT01511536). 
 
Given this new data and that the MTD of this combination was already established by the Massard 
study, we opted to change the orginal design of this trial in order not to duplicate the phase I that has 
already been established, and focus on  evalutatation of the efficacy of the combination in a more 
clinically relevant manner.  Therefore, this study is amended to 1) remove the phase I portion of the 
study; 2) change the phase II portion of the study to a randomized study comparing cabazitaxel alone 
to cabazitaxel in combination with abiraterone acetate at the MTD.  This revised design would be 
informative in that Arm A would inform the response to cabazitaxel monotherapy after prior 
abiraterone acetate treatment (currently not known since the TROPIC study was done in era when 
abiraterone acetate was not approved); and Arm B would evaluate whether the combination of 
cabazitaxel and abiraterone acetate can improve upon chemotherapy alone.   
2. 
STUDY OBJECTIVES 
2.1    
Primary Objectives 
 
To assess the anti-cancer efficacy of abiraterone acetate and cabazitaxel, compared with 
cabazitaxel alone, in patients with CRPC, as determined by progression-free survival at 3 
months. 
2.2    
Secondary Objectives 
 
To assess the anti-cancer activity of cabazitaxel vs. cabazitaxel with abiraterone acetate in 
patients with CRPC, after prior treatment with docetaxel and abiraterone acetate.  Efficacy 
will be determined by PSA response, maximum PSA decline at anytime during study 
treatment, time to PSA and radiographic progression, radiographic objective response, median 
progression-free survival, and overall survival. 
 
 
To assess ongoing safety and tolerability of the combination of abiraterone acetate and 
cabazitaxel.   
 
3. 
STUDY ENDPOINTS 
3.1    
Primary Endpoint 
Progression-free survival at 3 months in patients treated with cabazitaxel alone vs the 
combination of cabazitaxel with abiraterone acetate.  PFS is measured from the time of 
randomization until radiographic progression, clinical progression, or death due to any cause.   
3.2 
Secondary Endpoints 
 
Median progression-free survival.  The duration of PFS is measured from the time of 
randomization until radiographic progression, clinical progression, or death due to any cause.   
 
Overall survival.  Two year overall survival as defined as death due to any cause beginning 
with the time of randomization and continuing 2 years later based on assessment by telephone, 
email, or mail every 3 months. 
 
PSA response rate, defined as the proportion of patients achieving at least a 50% decline in 
PSA. Baseline PSA from screening or C1D1 will be used. 

 
16
 
Maximal PSA decline.  Baseline PSA from screening or C1D1 will be used.  PSA response 
will also be reported as the maximum PSA decline from baseline occurring at any time point 
on trial.   
 
Radiographic response rate.  Radiographic response from the time of randomization until 
radiographic progression as defined per RECIST 1.1 and protocol specific bone scan 
evaluation.   
 
Time to PSA progression, as defined in endpoint analysis as an increase in >25% from nadir 
occurring at least 12 weeks after start of therapy. 
 
Time to radiographic progression as measured from the time of randomization until protocol 
specific progression occurs based on CT and bone scans obtained every 12 weeks.   
 
Safety and tolerability as assessed by regular recording of toxicities via physical exam and 
laboratory analysis using the CTCAE v4.1 guidelines. 
 
4.    
STUDY DESIGN  
4.1    
Overview of Study Design 
This study is an open-label, randomized phase II study of abiraterone acetate in combination with 
cabazitaxel, compared with cabazitaxel alone, in patients with metastatic castrate-resistant prostate 
cancer who have previously been treated with docetaxel and abiraterone acetate (separately).  Thirty-
five patients will be enrolled in each arm of the study. 
Treatment will be administered over a 21-day cycle.  In both Arm A and Arm B, the cabazitaxel 
infusion will be administered intravenously on day 1 of each 21-day cycle.  In Arm B, abiraterone 
acetate will be taken orally daily on each day of the 21-day cycle.  Toxicity will be evaluated according 
to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 4.1.(27)   
AEs will be assessed; and laboratory values, vital signs, and physical exam will be obtained in order 
to evaluate the safety and tolerability of cabazitaxel +/- abiraterone acetate.  Patients will be evaluated 
with PSA every 3 weeks and radiographic imaging every 12 weeks.  Patients with at least stable disease 
will continue on study treatment until radiographic disease progression, unacceptable toxicity, or 
withdrawal of consent.   
4.2 
Duration of Study 
Patients will continue therapy until radiographic disease progression, development of unacceptable 
toxicities, non-compliance, intercurrent illness that prevents treatment continuation, withdrawal of 
consent, or change in subject condition that render the subject unacceptable for further treatment.  If a 
patient develops unacceptable toxicity related to one drug, but the patient has at least stable disease 
and ongoing clinical benefit, then the patient may be allowed to continue dosing with a single agent 
after discussion with the PI.  The End of Study (EOS) visit will occur within 30 days after the last dose 
of study drug, or prior to the start of subsequent anti-cancer therapy.  It is anticipated that enrollment 
for study will be 24-35 months and study duration will be approximately 48 months..  
4.3 
Overview of Drug Administration 
Table 3: Regimen Description 
 
REGIMEN DESCRIPTION 
 
Premedications; 
 
 
 
Cycle 

 
17
Agent 
Precautions 
Dose 
Route 
Schedule 
Length  
Cabazitaxel (Arm A 
and B) 
Premedicate with 
an antihistamine, 
steroid (8mg 
dexamethasone or 
equivalent 
steroid), and H2 
antagonist.  
Administered at 
least 30 minutes 
prior to each dose 
of cabazitaxel.   
25mg/m2  
in 500 cc 
NS or 
D5W 
IV over 1 
hours  
Day 1 
21 days  
(3 
weeks) 
Abiraterone acetate 
(Arm B) 
To be taken on an 
empty stomach* 
 1000mg  Orally once 
daily 
Day 1-21 
Pegfilgrastim≠ (Arm 
A and B) 
 
6mg 
subcutaneous 
Day 2 
Prednisone (Arm A 
and B) 
To be taken with 
food 
5mg 
Orally twice 
daily 
Day 1-21 
 
* To be taken on an empty stomach, at least two hours before the dose of abiraterone 
acetate and for at least one hour after the dose is taken 
≠ If pegfilgrastim is not covered by patient’s insurance, or not tolerated, then substitution with 
filgrastim per institutional guidelines will be allowed. 
 
 
4.4 
Criteria for Dose Administration 
4.4.1 
Study Drug Administration 
All protocol-specific criteria for administration of study drug must be met and documented prior to 
drug administration.  Cabazitaxel and abiraterone acetate will be administered only to eligible patients 
under the supervision of the investigator or identified sub-investigator(s).   
Cabazitaxel will be infused only after evaluation of blood chemistry and hematology results that must 
have been drawn within 24 hours prior to infusion.  
Abiraterone acetate will be administered on an empty stomach.  Patients should be instructed to refrain 
from eating and drinking (except for water and prescribed medications) for 2 hours before and 1 hour 
after each dose.    Each dose of abiraterone acetate will be taken orally with at least 8 ounces of water.   
Patients should be instructed to take their study medication at approximately the same time each day.  
In the event that a patient fails to take their abiraterone acetate doses within the time frame specified, 
or has an episode of emesis after study drug administration, the dose should be skipped and considered 
a missed dose.  Patients should record any missed doses in their dosing diary and resume dosing at the 
next scheduled time with the prescribed dosage.  

 
18
4.4.2 
Clinical Benefit 
Continuation on the trial is dependent on toxicities, as well as evidence of clinical benefit.  Patients 
must not have evidence of radiographic disease progression per RECIST 1.1 and modified Prostate 
Cancer Working Group 2 (PCWG2) bone scan evaluation criteria.  Efficacy assessments will be 
performed via imaging studies every 12 weeks.  Patients with progressive disease per RECIST 1.1 in 
combination with stipulations described in section 7.1 will be ineligible to receive further study 
treatment. 
4.5 
Dose Modification Guidelines 
 
Patients will be evaluated at the start of each cycle.  Patients may be evaluated more frequently at the 
discretion of the treating provider.  Toxicities are to be assessed according to the NCI CTCAE, version 
4.1.  Each AE should be attributed to a specific drug, if possible, so that the dose modifications can be 
made accordingly.  Reduction of one agent and not the other is appropriate if toxicity is attributable to 
just one of the agents.  Further clarification can be obtained in consultation with the principal 
investigator.  If multiple toxicities are noted, the dose adjustments and/or delays should be made 
according to the most severe toxicity guidelines.  The same dose modification guidelines will apply to 
maintenance cycles unless otherwise noted.  Guidelines for dose adjustments for hematologic and non-
hematologic toxicity are presented in Table 4. 
4.5.1 
Criteria for Toxicity Recovery Before Beginning the Next Cycle of Treatment 
If a patient fails to meet the criteria below for beginning the next cycle of treatment, initiation of the 
next cycle should be delayed.  At < 7 day’s time, the patient should be re-evaluated to determine 
whether the criteria for retreatment have been met.  Should the start of the next cycle need to be delayed 
for more than 2 weeks because of incomplete recovery from treatment-related toxicity, dose reduction 
should occur according to Table 4.   
In Arm B, if the AE is thought to be secondary to one drug alone, the non-offending agent may be 
restarted at the resolution of its respective toxicities.  The offending agent may then be resumed 
according to the appropriate dosage schedule at recovery of symptoms.  Criteria for Start of New Cycle 
in the Hematologic and Non-hematologic Recovery 
 
ANC must be ≥ 1,500/mm3. 
 
Platelet count must be ≥ 100,000/mm3. 
 
All other non-hematologic toxicity (except for alopecia, fatigue) must have resolved to 
≤ Grade 1, or to the patient’s baseline condition. 
4.5.2 
Criteria for Dose Modification (Delays, Reductions, and Discontinuations) 
Toxicities should be attributed to a specific study drug if possible so that dose modifications can be 
made rationally.  If multiple toxicities are noted, the dose adjustments and/or delays should be made 
once per cycle according to the most severe toxicity guidelines. 
4.5.3 
Guidelines regarding monitoring of patients while on abiraterone acetate 
The protocol design has incorporated the required monitoring parameters when treating patients on 
abiraterone acetate.  Please refer to the following guidelines for monitoring patients on abiraterone 
acetate: 
 
Hypertension 
- 
Control hypertension before and during treatment with Abiraterone Acetate.  Monitor blood 
pressure at least monthly.  

 
19
 
Hypokalemia 
- 
Correct hypokalemia before and during treatment with Abiraterone Acetate.  Monitor serum 
potassium at least monthly.  
 
Fluid Retention 
- 
Monitor for symptoms of fluid retention at least monthly. 
 
Adrenocortical Insufficiency 
- 
Monitor for symptoms and signs of adrenocortical insufficiency.   
 
- 
Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly 
if patients are withdrawn from prednisone, have prednisone dose reductions, or experience 
unusual stress.  Symptoms and signs of adrenocortical insufficiency may be masked by 
adverse reactions associated with mineralocorticoid excess seen in patients treated with 
Abiraterone Acetate.  If clinically indicated, perform appropriate tests to confirm the diagnosis 
of adrenocortical insufficiency.  Increased dosage of corticosteroids may be indicated before, 
during and after stressful situations. 
 
Hepatotoxicity 
- 
Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment 
with Abiraterone Acetate, every two weeks for the first three months of treatment and monthly 
thereafter.   
- 
Promptly measure serum total bilirubin, AST, and ALT, if clinical symptoms or signs 
suggestive of hepatotoxicity develop. 
- 
Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent 
monitoring.  
- 
For subjects with baseline hepatic impairment or those that develop hepatotoxicity, please 
refer to Mandatory Dose Modification Guidelines.  
 
4.5.4    
Dose Adjustments for Hematologic and Non-Hematologic Toxicity:  
A decision regarding which study drug requires dose reduction will be dependent upon the toxicity, its 
onset, and time course.  Alternative dose modifications may be recommended after discussion with 
the investigator in order to maximize exposure of study treatment while protecting patient safety.  
Guidelines for dose adjustments for hematologic and non-hematologic toxicity are presented in Table 
4. 
Table 4:  Dose Adjustment for Hematologic and Non-hematologic toxicity 
Adverse Event 
NCI CTC Grade 
Immediate Action 
Dose Adjustments 
THROMBOCYTOPENIA – Platelet count decreased 
 
Grade 3 with clinically 
significant bleeding or Grade 4 
< 25,000/mm3 
 
Hold treatment with 
cabazitaxel and continue 
abiraterone acetate 
1st occurrence: Decrease 
cabazitaxel to 20 mg/m2 
2nd occurrence: decrease 

 
20
Check CBC at least weekly 
cabazitaxel to 15 mg/m2.   
3rd occurrence: Stop 
cabazitaxel.  Withdraw from 
study if Arm A.  After 
discussion with PI, Arm B 
patients may continue 
abiraterone acetate alone if no 
radiographic progression and 
clinically benefitting.  
NEUTROPENIA - Neutrophil count (ANC) decreased 
 
Grade 3 or 4 
or 
> Grade 3 with fever 
(temperature > 38.3C) 
 
 
Hold cabazitaxel and 
continue abiraterone acetate 
 
Follow CBC with 
differential at least weekly 
 
 
Do not dose next cycle of 
cabazitaxel until 
neutropenia is resolved to 
grade < 1 
 
1st occurrence: 
Decrease cabazitaxel to 
20 mg/m2 
 
2nd occurrence: 
decrease cabazitaxel to 
15 mg/m2.   
 
3rd occurrence: Stop 
cabazitaxel.  Withdraw 
from study if Arm A.  
After discussion with 
PI, Arm B patients may 
continue abiraterone 
acetate alone if no 
radiographic 
progression and 
clinically benefitting. 
ANEMIA – Hemoglobin decreased 
Grade 3 or 4  
 
Hold cabazitaxel and 
transfuse as appropriate 
 
Wait until recovery to 
grade ≤ 2 prior to 
retreatment with 
cabazitaxel. 
 
1st occurrence: 
Decrease cabazitaxel to 
20 mg/m2 
 
2nd occurrence: 
decrease cabazitaxel to 
15 mg/m2.   
 
3rd occurrence: Stop 
cabazitaxel.  Withdraw 
from study if Arm A.  
After discussion with 
PI, Arm B patients may 
continue abiraterone 
acetate alone if no 
radiographic 
progression and 
clinically benefitting. 

 
21
HYPERTENSION – Blood pressure elevated 
Grade 3 and systolic blood 
pressure >20mm Hg higher 
than baseline OR diastolic 
blood pressure >10 mm Hg 
higher than baseline 
 
 
 
 
 
Add additional anti-
hypertensives or increase 
dose of existing anti-
hypertensives 
 
If not controlled to <140/90 
mm Hg with maximum 
medications, hold 
treatment with abiraterone 
acetate until controlled and 
restart at 1 dose level 
reduction (decrease by 
250mg/day) 
Grade 4 
 
Discontinue treatment 
 
Do not continue treatment 
with abiraterone acetate 
DIARRHEA 
Grade 2 
 
 
 
Begin treatment anti-
diarrheal agents per local 
standard of care 
 
If Grade 2 diarrhea persists 
despite maximal supportive 
therapy, hold both drugs 
until resolution to grade <1 
and reduce cabazitaxel by 1 
dose level. 
Grade 3 
 
Hospitalization may be 
indicated 
 
 
Hold both drugs until 
symptoms resolve to grade 
<1 and restart each at one 
dosage level reduction. 
Grade 4 
 
Hospitalization likely 
indicated 
 
Stop cabazitaxel.  Once 
symptoms resolve to grade 
< 1 restart abiraterone 
acetate at 1 dose level 
reduction.  At second 
occurrence, discontinue 
abiraterone acetate. 
NAUSEA AND VOMITING 

 
22
Grade 3 (except): 
 
> Grade 3 nausea 
and/or emesis in the 
absence of optimal 
anti-emetic prophylaxis  
 
 
Hold cabazitaxel and 
abiraterone acetate until 
resolution to Grade < 1 or 
baseline.   
 
HEPATOTOXICITY -  Transaminase Elevation, Bilirubin Elevation) 
Please note full text of dose alterations is following this chart 
Grade 3  
 
Hold abiraterone acetate 
 
If recover to Grade < 2 
transaminitis, grade <1 
hyperbilirubinemia, or 
baseline, restart at one dose 
level reduction of 
abiraterone acetate.  For 
patients who resume 
treatment, monitor LFTs at 
least every 2 weeks for 3 
months and monthly 
thereafter. 
 
On second occurrence, if 
recovery to Grade <1, or 
baseline, restart at one dose 
level reduction of both 
medications.   
 
On third occurrence, 
discontinue abiraterone. 
Grade 4 
 
Hold both drugs 
 
If recovery to Grade <1 or 
baseline, restart both drugs 
at one dose level reduction.  
Patients will then need 
LFTs checked every 2 
weeks for 3 months and 
monthly thereafter.  The 
safety of abiraterone 
acetate re-treatment of 
patients who develop grade 
4 toxicity is unknown. 
HYPOKALEMIA 
Grade 2 
 
Begin oral potassium 
supplementation.  Recheck 
at weekly intervals and 
adjust potassium dose as 
necessary 
 

 
23
Grade 3 
 
 
Hold abiraterone acetate. 
 
Increase oral repletion.   
 
Recheck at least weekly 
until replete. 
 
Hospitalization may be 
indicated. 
  
 
If unable to replete to grade 
<1 within 2 weeks, 
decrease dose of 
abiraterone acetate by 1 
dose level.   
 
If recurs, or again, unable 
to replete to grade <1 
within 2 weeks decrease by 
an additional dose level. 
 
If unable to fully replete to 
grade <1 after above 
adjustments, discontinue 
drug. 
Grade 4 
 
Hold abiraterone acetate.   
 
Hospitalization may be 
indicated. 
 
Begin IV repletion in a 
monitored setting.  Replete 
to at least grade <2 before 
resuming abiraterone 
acetate.   
 
If unable to replete to grade 
<1 within 2 weeks, 
decrease dose of 
abiraterone acetate by 1 
dose level.   
 
If recurs, or again, unable 
to replete to grade <1 
within 2 weeks decrease by 
an additional dose level. 
 
If unable to fully replete to 
grade <1 after above 
adjustments, discontinue 
drug. 
CARDIOTOXICITY 

 
24
QTc 
Increase of 15ms-20ms from 
baseline 
 
Increase of >20ms from 
baseline 
 
 
Repeat EKG in one week 
 
 
Hold drug for 1 week, 
repeat EKG within 10 days 
 
 
If not increased, no change 
 
 If not decreased below 
20ms change, patient must 
withdraw.  If decreased, 
recheck in 1 week to 
confirm 
Abbreviations:  ANC = absolute neutrophil count; CBC = complete blood count; G-CSF = 
granulocyte colony stimulating factor; NCI CTC = National Cancer Institute Common Terminology 
Criteria.   
Specific Instructions on Hepatotoxicity: 
Hepatotoxicity 
 
For patients who develop hepatotoxicity during treatment with ZYTIGA (ALT and/or AST greater 
than 5X ULN or total bilirubin greater than 3X ULN), interrupt treatment with ZYTIGA Treatment 
may be restarted at a reduced dose of 750 mg once daily following return of liver function tests to the 
patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or 
equal to 1.5X ULN.  For patients who resume treatment, monitor serum transaminases and bilirubin 
at a minimum of every two weeks for three months and monthly thereafter.  
 
If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be restarted at a reduced 
dose of 500 mg once daily following return of liver function tests to the patient’s baseline or to AST 
and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. 
 
If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment with ZYTIGA.  
The safety of Abiraterone Acetate re-treatment of patients who develop AST or ALT greater than or 
equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. 
 
Table 5: Treatment of Cabazitaxel associated hypersensitivity reactions:  A cabazitaxel associated 
hypersensitivity reaction will likely occur within minutes of the start of the infusion.   
SYMPTOM SEVERITY 
INTERVENTION RECOMMENDATION 
Mild symptoms: cutaneous flushing, rash, 
pruritus 
 
Decrease rate of infusion until recovery 
 
Once resolved, may increase to initial rate 
Moderate: generalized flushing, rash, dyspnea, 
back pain during infusion, systolic hypotension 
 
Give diphenhydramine 50 mg IV and/or 
dexamethasone 10mg IV or equivalent. 
 
Resume infusion within 3 hours of recovery 
of symptoms 
 
Slow all future infusions to 2 hours 
Severe: bronchospasm, urticaria, systolic blood 
pressure <80 mmHg 
 
Stop the infusion 
 
Give diphenhydramine 50mg IV and/or 
dexamethasone 10mg IV (or equivalent) 
and or epinephrine 

 
25
 
Wait at least 3 hours and for full recovery 
of symptoms prior to considering 
rechallenge. 
 
If recurrent severe reaction at rechallenge, 
withdraw patient from study 
Anaphylaxis 
 
Remove from protocol 
 
5.    
STUDY POPULATION 
5.1    
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 
Written informed consent has been obtained. 
 
Adults over 18 years of age. 
 
Histologically or cytologically proven adenocarcinoma of the prostate.  
 
Stage IV disease as evidenced by soft tissue, visceral and/or bony metastasis must be RECIST 
evaluable on CT scan and/or bone scan 
 
Progressive disease while receiving hormonal therapy or after surgical castration documented 
by at least one of the following: (1) Increase in measurable disease per RECIST 1.1, (2) 
Appearance of new lesions on bone scan consistent with progressive prostate cancer (>2 new 
lesions on bone scans if this is the only measure of PD), (3) rising PSA defined as 2 sequential 
increases above a previous lowest reference value.  Each value must be obtained at least 1 
week apart.   
 
PSA at least 2 ng/mL 
 
Received prior docetaxel chemotherapy 
 
Received prior abiraterone acetate, but not within the 3 months prior to study drug dosing.  
 
Testosterone level <50 ng/dL.  Patients receiving LHRH agonists or antagonists must be 
continued to maintain castrate levels of testosterone while on study. 
 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 
 
Adequate hematologic function (platelet >100, 000/uL; neutrophil count of >1500 cell/mm3; 
hemoglobin >9.0 g/dL) 
 
Adequate renal function (Creatinine < 1.5 X ULN or creatinine clearance > 50 mL/min)  
 
Adequate potassium level > 3.5 mEq/dL 
 
Adequate hepatic function (bilirubin < 1.5 X upper limit of normal (ULN), alanine 
aminotransferase (ALT) < 1.5 X ULN, aspartate aminotransferase (AST) < 1.5 X ULN.  Have 
a serum albumin of ≥ 3.0 g/dL 
 
Controlled blood pressure, defined as blood pressure ≤ 140/90 on average (3 separate readings 
taken at screening visit in a relaxed clinical environment and averaged) 
 
Must be able to take oral medication without crushing, dissolving or chewing tablets 
 
Willing to take abiraterone acetate on empty stomach; no food should be consumed at least 
two hours before and for at least one hour after the dose of abiraterone acetate is taken 

 
26
 
Patients must be willing and able to adhere to the prohibitions and restrictions specified in this 
protocol. 
 
Written authorization for use and release of health and research study information has been 
obtained. 
 
Patients who have partners of childbearing potential must be willing to use a method of birth 
control with adequate barrier protection during the study and for 1 week after the last dose of 
abiraterone acetate. 
5.2 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
 
Surgery or radiation therapy within 2 weeks.  Cytotoxic anti-cancer therapy within 3 weeks.  
Non-cytotoxic anti-cancer therapy within 2 weeks, or 5 half-lives (whichever is shorter) of 
Study Day 1.  
 
Prior radiotherapy to ≥ 40% of bone marrow. 
 
Use of an investigational therapeutic agent within 30 days 
 
Have a history of gastrointestinal disorders (medical disorders or extensive surgery) that may 
interfere with the absorption of the study agents 
 
Prior treatment with cabazitaxel 
 
Known chronic infection with human immunodeficiency virus (HIV) 
 
Known active, or symptomatic, brain metastasis 
 
Blood pressure >140/90 mm/Hg on average (3 separate readings taken at screening visit in a 
relaxed clinical environment and averaged) 
 
Baseline peripheral edema > grade 3 
 
Pre-existing diarrhea uncontrolled with supportive care; prior hemorrhagic diarrhea due to 
ulcerative colitis, inflammatory bowel disease or other cause; active, uncontrolled peptic ulcer 
disease even in the setting of proton-pump inhibitor or Histamine2-blocker use. 
 
Pre-existing peripheral neuropathy grade > 2  
 
Documented hypersensitivity (CTCAE grade > 2) to any drug containing polysorbate 80 
 
Have known allergies or hypersensitivity to abiraterone acetate or prednisone or their 
excipients 
 
Contraindications to steroid use 
 
Need for medications that strongly induce or inhibit CYP3A4 or CYP2D6 activity.  See 
section 7.2.3 for details 
 
Serious infection requiring parenteral antibiotics within 14 days of enrollment 
 
Poorly controlled diabetes (Hgb A1C >9) 
 
Active or symptomatic viral hepatitis or chronic liver disease, including Child-Pugh Class B 
and C liver disease. 
 
History of pituitary or adrenal dysfunction 

 
27
 
Clinically significant heart disease as evidenced by myocardial infarction, or arterial 
thrombotic events in the past 6 months, severe or unstable angina, or New York Heart 
Association Class III-IV heart disease or cardiac ejection fraction measurement of <50% at 
baseline. 
 
Consumption of food or beverages containing grapefruit juice within 7 days of study drug 
dosing 
 
Use of a first-generation anti-androgen such as bicalutamide within 6 weeks of study drug 
dosing, or flutamide within 4 weeks of study dosing.   
 
Have any condition that, in the opinion of the investigator, would compromise the well-being 
of the subject or the study or prevent the subject from meeting or performing study 
requirements 
 
6. 
STUDY PROCEDURES AND ASSESSMENTS 
The schedule of assessments is summarized in Table 1. 
6.1 
Informed Consent 
Enrollment in the study requires that all inclusion and exclusion criteria have been met.  A patient may 
be enrolled into the study when the written informed consent has been obtained and the patient’s 
eligibility per all inclusion and exclusion criteria has been confirmed. 
6.2 
Study Visits 
Patients will be evaluated at scheduled visits over the following study periods:  Screening, Treatment, 
and EOS.  Evaluations during the Screening period are to be conducted within 28 days before 
administration of the first dose of cabazitaxel and abiraterone acetate.  Bone scan and CT scan 
evaluations performed within 6 weeks of Cycle 1 Day 1 are acceptable.  Unless otherwise noted, 
evaluations during the Treatment period must occur before study drug administration.  Tests and 
procedures should be performed on schedule for all visits. Occasional changes are allowable with 
permission for holidays, vacations, and other administrative reasons.   
All EOS evaluations should occur within 30 days after the last dose of study drug, or prior to the start 
of subsequent anti-cancer therapy, whichever is earlier. 
6.2.1 
Physical Examination 
A complete physical examination will be performed before dosing on Day 1 of each cycle and at the 
end of treatment.  Vital signs (temperature, blood pressure, pulse rate, respiratory rate, and weight) 
will be performed at each visit.  ECOG performance status will be evaluated at day 1 of each cycle 
and end of study.  Clinically significant AEs will be captured as well. 
 
 
6.2.2 
Schedule of Events Arm A and Arm B 
 
Screening/Baseline (Days -28 to 0) 
 
Informed consent and HIPAA 
 
Study eligibility per inclusion/exclusion criteria 
 
Medical history/baseline conditions 
 
Physical examination 

 
28
 
Vital signs, including height and weight 
 
ECOG performance status 
 
ECG 
 
Blood samples for hematology, comprehensive metabolic panel 
 
Serum PSA  
 
Serum Testosterone 
 
Blood sample for HA1C 
 
CT scan and assessment of tumor burden 
 
Bone scan 
 
Collection of concomitant medications 
 
Collection of adverse events 
 
Day 1 of each cycle 
 
Physical examination and history 
 
Vital signs 
 
ECOG performance status 
 
ECG for cycle 2 
 
Blood samples for hematology, comprehensive metabolic panel 
 
Serum PSA 
 
CT and bone scan to be performed every 12 weeks 
 
Collection of concomitant medications 
 
Collection of adverse events 
 
Cycle 1-4 Day 15 visits 
Liver function test lab visit (Arm B only) 
 
7. 
STUDY ASSESSMENTS 
7.1 
Efficacy Evaluations 
The primary endpoint is progression-free survival at 3 months in patients treated with cabazitaxel alone 
vs the combination of cabazitaxel with abiraterone acetate.  PFS is measured from the time of 
randomization until radiographic progression per RECIST 1.1, clinical progression, or death due to 
any cause.     
 
The secondary endpoints include:  
 
Median progression-free survival.  The duration of PFS is measured from the time of 
randomization until radiographic progression, clinical progression, or death due to any cause.     
 
Overall survival.  Two year overall survival as defined as death due to any cause beginning 
with the time of randomization and continuing 2 years later based on assessment by telephone, 
email, or mail every 3 months. 
 
PSA response rate, defined as the proportion of patients achieving at least a 50% decline in 
PSA. Baseline PSA from screening or C1D1 will be used. 
 
Maximal PSA decline.  Baseline PSA from screening or C1D1 will be used.  PSA response 
will also be reported as the maximum PSA decline from baseline occurring at any time point 
on trial.   
 
Radiographic response rate.  Radiographic response from the time of randomization until 
radiographic progression as defined per RECIST 1.1 and protocol specific bone scan 
evaluation.   

 
29
 
Time to PSA progression, as defined in endpoint analysis as an increase in >25% from nadir 
occurring at least 12 weeks after start of therapy. 
 
Time to radiographic progression as measured from the time of randomization until protocol 
specific progression occurs based on CT and bone scans obtained every 12 weeks.   
 
Safety and tolerability as assessed by regular recording of toxicities via physical exam and 
laboratory analysis using the CTCAE v4.1 guidelines. 
 
Patients will be removed from study if they have evidence of radiographic disease progression as 
defined below.  Radiographic analysis via CT scan and bone scan will occur at baseline and every 12 
weeks after the initiation of study treatment.  CT scans should be performed with cuts of 10mm or less 
in slice thickness contiguously.  For the purposes of this study, investigators should utilize the 
protocol-specified tumor assessment criteria, defined as assessment of evaluable soft tissue disease 
sites according to RECIST (version 1.1), and/or assessment of bone disease.  Bone disease progression 
will be defined as the development of one new lesion at the first imaging analysis that is confirmed 
with an additional lesion 6 weeks later.  Subsequent to cycle 4, bone scan progression will constitute 
the appearance of two or more new bone lesions from baseline.  Increase in intensity of known bone 
lesions will not constitute progression.  The date of progression will be recorded as the date the first 
scan shows change.  Soft tissue response will be evaluated as follows:  
Target lesions 
Nontarget lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
PSA response will be evaluated for endpoint analysis, but will not be a contributor to the ongoing 
measurement of response or progression to determine treatment continuation throughout the study.  
Thus, PSA progression alone, in the absence of radiographic progression, does not necessitate removal 
from study treatment, and treatment in the setting of PSA rise is allowable at the discretion of the 
investigator.  Progression-free survival is measured from the date of randomization to the date of 
radiographic progression, clinical progression, or until death from any cause.   
7.2 
Safety Evaluations 
The investigator will oversee the care and safety of all subjects enrolled in the trial.  Study visits occur 
every 21 days, more frequently at investigator discretion, and will include monitoring and recording 
all adverse events and serious adverse events; regular monitoring of hematology, blood chemistry, 

 
30
hepatic function; ECG assessment for cycles 1-3; regular measurement of vital signs, physical 
examination including weight and performance status.  Safety and tolerability will be assessed using 
the CTCAE v4.1 guidelines. 
7.2.1 
Adverse Events 
Monitoring of AEs will be conducted throughout the study.  AEs will be reported from the date written 
informed consent is obtained and through 30 days post-last dose of study drug.  Serious pretreatment 
events will be reported to the Janssen Scientific Affairs designee from the time of the signing of the 
Informed Consent Form (ICF) up to first dose of study drug.  SAEs will be reported to the Janssen 
Scientific Affairs designee from the date written informed consent is obtained through 30 days after 
administration of the last dose of study drug.  All SAEs will be monitored until they are resolved or 
are clearly determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
7.2.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed locally.  Blood chemistry and hematology tests 
performed within 5 days of Cycle 1 Day 1 do not need to be repeated before dose 1 administration.  
For subsequent cycles, chemistry and hematology results must be drawn and reviewed within 24 hours 
prior to all cabazitaxel infusions.   
7.2.3 
Concomitant Medication and Therapies 
Abiraterone acetate is a strong inhibitor of CYP2D6, CYP1A2, and CYP2C8.  It is a moderate inhibitor 
of CYP2C9, CYP2C19 and CYP3A4/5 and thus may influence the metabolism of other CYP2D6 
substrates.  Additionally, abiraterone acetate is a substrate of CYP2A4 and thus medications which 
inhibit or induce this enzyme may influence the metabolism of abiraterone acetate. 
Effects of Abiraterone on Drug Metabolizing Enzymes 
 
Abiraterone Acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6.  In a CYP2D6 
drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were 
increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 
1,000 mg daily and prednisone 5 mg twice daily.  Avoid co-administration of abiraterone acetate with 
substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).  If alternative treatments 
cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate 
drug  
 
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 
substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg 
abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a 
CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA. 
 
Drugs that Inhibit or Induce CYP3A4 Enzymes 
 
Based on in vitro data, Abiraterone Acetate 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.   
 
The following medications and procedures are PROHIBITED during the study: 

 
31
 
Any anti-cancer therapies other than abiraterone acetate and cabazitaxel 
 
Any investigational therapies other than abiraterone acetate and cabazitaxel 
 
Strong inducers/inhibitors of CYP3A4 or CYP2D6: dextromethorphan, ketoconazole, 
itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycine, ritonavir, 
indinavir, neflinavir, voriconazole, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 
and phenobarbital.   
 
In addition to the above medications, grapefruit juice or grapefruit juice products should be 
avoided. 
 
The following medications and procedures are ALLOWED during the study: 
 
LHRH agonists or antagonists are acceptable while on trial 
 
Bisphosphonates or denosumab are allowed 
 
5- alpha- reductase inhibitors are allowable for patients treated > 2 months prior to study 
enrollment, with continued PSA rise through this treatment 
 
Use of colony-stimulating factors are allowed  
 
Palliative radiotherapy to a bone lesion that was present at baseline. 
 
7.2.4 
Completion of Study 
Patients will be considered to have completed the study if they (1) have received at least 1 cycle of 
treatment, AND (2) experienced progressive disease, OR (3) experienced unacceptable toxicity.  In 
the absence of progressive disease radiographically or unacceptable toxicity, and in the setting of 
continued clinical benefit, patients may be permitted to remain on therapy upon discussion with the 
PI.   
 
7.2.5    
Withdrawal of Patients from Study  
Patients will be informed that they have the right to withdraw from study treatment at any time for any 
reason, without prejudice to their medical care.  A patient may be withdrawn from study treatment for 
any of the following reasons:   
 
Adverse Event 
 
Protocol Violation 
 
Radiographic Progressive Disease as defined in section 7.1 
 
Symptomatic Deterioration 
 
Study Terminated by the University of Colorado Cancer Center 
 
Withdrawal by Subject 
 
Lost to Follow-up 
 
Other 
At the time of study drug discontinuation, all study procedures outlined for the EOS visit should be 
completed within 30 days after the last dose of study drug.  The primary reason for a patient’s 
withdrawal from the study is to be recorded. 

 
32
The consequence of withdrawal of consent by a patient will be that no new information will be 
collected from that patient and added to the existing data or any database.  However, every effort will 
be made to follow all patients for safety. 
7.3    
Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s).  The appropriate study personnel will maintain records 
of study drug receipt and dispensing, including the following:  applicable lot numbers and total drug 
administered in milligrams (mg).  Any discrepancy regarding the dose administered and the reason for 
the discrepancy will be noted. 
Patients will receive a sufficient quantity of abiraterone acetate for each treatment cycle.  The study 
center staff will check the patient’s diary versus the patient’s supply of remaining abiraterone acetate 
tablets at each study visit to ensure proper compliance with dosing.  At the discretion of the treating 
physician, patients who are not compliant with the dosing schedule (e.g. miss more than 50% of the 
study medication dosing) may be withdrawn from the study. 
 
8. 
INVESTIGATIONAL AGENTS 
 
8.1 
Precautions and Restrictions  
In general, patients receiving concomitant medications, particularly those with narrow therapeutic 
indices, should be carefully monitored, as potential drug-drug interactions between the combination 
of cabazitaxel, abiraterone acetate, and other drugs have not been studied in humans.  Patients should 
be instructed to consult with the investigator before taking any new medications, including over-the-
counter and herbal products.  Patients should be instructed to limit the use of alcohol while enrolled in 
this study. 
8.2 
Description of Investigational Agents 
8.2.1    
Abiraterone acetate 
The drug product is labeled abiraterone acetate.  Each tablet contains 250 mg of active abiraterone 
acetate.  Inactive ingredients in the tablets are lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, and colloidal silicon 
dioxide.  Please refer to the package insert for further details. 
 
8.2.2 
Cabazitaxel 
Cabazitaxel injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow 
viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and 
solvent free) and 1.56 g polysorbate 80.  Cabazitaxel is to be mixed with a diluent that is a clear, 
colorless, sterile, and non-pyrogenic solution containing 13% ethanol in water for injection, 
approximately 5.7 mL.  Cabazitaxel requires two dilutions prior to intravenous infusion and should 
only be diluted with the supplied diluent with the second dilution in 0.9% sodium chloride solution or 
5% dextrose solution.  Both items are in a blister pack in one carton.  Please refer to the package insert 
for further details. 
 
8.2.3 
Prednisone 
Please refer to post-marketing product information on prednisone. 
 
8.2.4 
Pegfilgrastim 
Please refer to post-marketing product information on pegfilgrastim. 
 

 
33
8.2.5 
Filgrastim 
Please refer to post-marketing product information on filgrastim. 
 
 
8.3    
Preparation, Reconstitution, and Dispensation 
The University of Colorado Cancer Center clinical trials team and the PI will assign each patient who 
signs a consent form a patient number.  Patients will be randomized by the statistician involved with 
this study to either Arm A or Arm B.  Patients in Arm B will be dispensed bottles of study drug 
containing an appropriate number of tablets.Preparation and reconstitution of cabazitaxel will be 
performed according to section 8.2.2 above. 
All unused study drug and the amount of study drug returned will be recorded on the drug 
accountability form.  Patients will be instructed to store the abiraterone acetate tablets only in the 
bottles dispensed.  Patients will be given a diary with instructions to record each study drug dose 
whether taken or missed.   
8.4 
Storage, Handling, Accountability 
8.4.1 
Cabazitaxel 
Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).  Do not refrigerate.  For 
additional details please consult the full prescribing information. 
8.4.2 
Abiraterone acetate 
Store at 20oC to 25oC (68oF to 77oF); excursions permitted to 15oC to 30oC (59oF to 86°F).  For 
additional details please consult the full prescribing information. 
8.4.3 
Handling and Accountability 
This medicine may cause harm to the unborn child if taken by women who are pregnant. It should not 
be taken by women who are breast-feeding. Women who are pregnant or who may be pregnant should 
wear gloves if they need to touch abiraterone acetate tablets. Study staff and caregivers should be 
notified of this information, to ensure the appropriate precautions are taken. 
 
All clinical drug supplies must be kept in an appropriate, limited-access, secure place until used or 
destroyed.  The investigator must maintain 100% accountability for all study medication received and 
dispensed.  Proper drug accountability includes, but is not limited to:   
 
Frequently verifying that actual inventory matches documented inventory 
 
Verifying that the log is completed for the drug lot used to prepare each dose 
 
Verifying that all containers used are documented accurately on the log 
 
Verifying that required fields are completed accurately and legibly 
If any dispensing errors or discrepancies are discovered, the PI must be notified immediately. 
The investigator must maintain a current inventory of all study medication delivered to the site, 
inventory at the site, and records of patient use.  This log must accurately reflect the drug accountability 
of the study medication at all times.  The following information will be recorded at a minimum:  
protocol number and title, name of investigator, site identifier and number, description of study 
medication, expiration date, date and amount dispensed, and the date and amount returned to the site 
by the patient, including the initials of the person dispensing and receiving the study medication.  The 
log should include all required information as a separate entry for each patient to whom study 
medication is dispensed. 
Before site closure, or at appropriate intervals, a representative from the PI or its designee will perform 
clinical study material accountability and reconciliation before clinical study materials are destroyed.  

 
34
The investigator will retain the original documentation regarding clinical study material accountability 
and destruction. 
The investigational pharmacy will monitor any expiration date and subsequently segregate and destroy 
expired clinical study drug.  
 
9.    
STUDY CONDUCT 
This trial will be conducted in compliance with the protocol, good clinical practice (GCP), applicable 
regulatory requirements, and International Conference on Harmonisation (ICH) guidelines. 
9.1    
Arrangements for Recruitment of Patients 
Recruitment and enrollment strategies for this study may include recruitment from the investigator’s 
local practice or referrals from other physicians.  If advertisements become part of the recruitment 
strategy, they will be reviewed by the institutional review board (IRB)/independent ethics committee 
(IEC).  It is not envisioned that prisoners (or other populations that might be subject to coercion or 
exploitation) will be enrolled into this study. 
9.2    
Treatment Group Assignments  
Stratified randomization (bone metastasis only vs bone and soft tissue metastasis, presence/absence of 
visceral disease) will be performed by the statistician for this trial. 
 
10. 
STATISTICAL AND QUANTITATIVE ANALYSES 
10.1    
Statistical Methods 
A University of Colorado Anschutz Campus statistician will perform the data analysis for this trial.  
Janssen Scientific Affairs will not have a decisional role in the analysis or writing of any resultant 
manuscripts. 
This is a randomized 2 arm study.  Arm A will be the standard of care arm of cabazitaxel alone.  Arm 
B will be the investigational arm combining cabazitaxel and abiraterone.   All patients will have 
received prior docetaxel and prior abiraterone acetate.  The primary endpoint will be proportion that 
is progression free at 3 months.  From the registration trial of cabazitaxel vs. mitoxantrone (TROPIC), 
the median PFS was 2.8 months, and PFS at 3 month for the cabazitaxel arm was 47.6%.   
 
10.1.1 
Sample Size 
The goal of this trial is to estimate the proportion that is progression free at 3 months for each of the 
two arms with a pre-specified precision (80% confidence limits are within 12% of the rate).  Given 
that all the subjects in this trial will have had prior exposure to abiraterone acetate, whereas patients in 
the TROPIC trial were not pretreated with abiraterone acetate, we would assume that the median PFS 
is at least 2.8 months in either arm.  The table below summarizes the 80% confidence limits for the 
proportion of proportion that is progression free at 3 months with several potential median PFS values.  

 
35
 
Median 
PFS 
(months) 
Percentage (%) 
increase from 
2.8 months 
 Proportion 
that 
is 
progression 
free 
at 
3 
months  (%) 
80% CI  
With 
35 
subjects 
per 
arm 
2.8 
- 
0.48 
0.37, 0.61 
3.1 
10 
0.51 
0.39, 0.63 
3.36 
20 
0.54 
0.42, 0.66 
3.64 
30 
0.57 
0.45, 0.69 
3.92 
40 
0.59 
0.48, 0.71 
4.2 
50 
0.61 
0.49, 0.73 
 
10.1.2 
Aim Analysis 
Primary Aim 
The primary endpoint is progression-free survival at 3 months in patients treated with cabazitaxel alone 
vs the combination of cabazitaxel with abiraterone acetate.  PFS is measured from the time of 
randomization until radiographic progression, clinical progression, or death due to any cause.    The 
probability distributions for PFS will be calculated using the Kaplan-Meier method, all measured from 
the time of randomization.  The 3 month PFS estimates will be obtained from the probability 
distributions. 
 
Secondary Aims 
The secondary endpoints include median progression-free survival, duration of PFS, overall survival, 
PSA response rate, maximal PSA decline, radiographic response rate, time to PSA progression, time 
to radiographic progression, and safety and tolerability.  See section 7.1 for definitions of each 
outcome.  The probability distributions for the PFS and OS outcomes will be calculated using the 
Kaplan-Meier method, all measured from the time of randomization.  The median point estimates will 
be obtained from these probability distributions and presented with 95% confidence intervals.  PSA 
and radiographic endpoints will be presented graphically using a waterfall plot or in tabular form.  
Adverse events data will be analyzed using tables and descriptive statistics. 
10.1.3 
Accrual 
The study center treats approximately 4-5 patients monthly who would be eligible for enrollment in 
the trial.  We estimate that 2-3 patients will enroll a month.   
10.2 
Safety Population 
The safety population is defined as all patients who receive at least 1 dose of either abiraterone acetate 
OR cabazitaxel.  This population will be used for all safety analyses as well as efficacy analyses. 

 
36
10.3 
PSA Response Evaluable Population 
The PSA response-evaluable population is defined as all patients who receive at least 1 dose of either 
study drug, have a baseline PSA measurement, and have 1 post-baseline PSA assessment.  This 
population will be used for analyses of response. 
10.4 
Tumor-Response Evaluable Population 
The response-evaluable population is defined as all patients who receive at least 1 dose of either study 
drug, have RECIST 1.1 evaluable bone metastasis or RECIST 1.1 evaluable soft tissue metastasis at 
baseline, and have 1 post-baseline disease assessment.  This population will be used for analyses of 
response. 
 
11. 
SAFETY ANALYSIS 
11.1 
  
The safety population will be used for the analysis of the toxicities and AEs in the study.  In addition, 
to assess the relationship between toxicities and cabazitaxel in combination with abiraterone acetate, 
the preferred term of individual toxicities will be summarized by their frequency and intensity for each 
dose group. 
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, and clinical laboratory results using the safety population.  
Exposure to study drug and reasons for discontinuation will be tabulated. 
Treatment related AEs that occur after administration of the first dose of study drug and through 30 
days after the last dose of study drug will be tabulated.  AEs will be tabulated according to the Medical 
Dictionary for Regulatory Activities (MedDRA) and will include the following categories:  
 
Drug-related AEs 
 
Grade 3 or higher AEs 
 
Grade 3 or higher drug-related AEs 
 
The most commonly reported treatment-emergent AEs (i.e., those events reported by  10% 
of all patients)  
 
SAEs 
A listing of AEs resulting in study discontinuation will be provided. 
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over time.  
All concomitant medications collected from screening through the study period will be classified to 
preferred terms according to the World Health Organization (WHO) drug dictionary. 
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of cabazitaxel with abiraterone acetate. 
 
12.    
ADVERSE EVENTS 
12.1 
Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with this 

 
37
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 
 
Adverse Events of Special Interest 
Events that Janssen Scientific Affairs are actively monitoring, as a result of a previously 
identified signal (even if non-serious) and are typically defined in the Protocol.  
 
 
Events of special interest include:  
 
Mineralocorticoid excess (Hypertension, Hypokalemia, Fluid retention) 
 
Hepatotoxicity 
 
Cardiac disorders 
 
Osteoporosis including osteoporosis-related fractures 
 
Increased exposure with food 
 
Rhabdomyolysis/myopathy 
 
Drug-drug interaction (CYP2D6) 
 
Allergic alveolitis 
 
 
Adverse Drug Reaction (ADR) 
A noxious and unintended response to any dose of the drug (or biological) product for which 
there is a reasonable possibility that the product cause the response.  ‘‘Reasonable possibility’’ 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event.  Suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any adverse event caused by a drug. 
J&J Medicinal Product 
The specific Johnson & Johnson drug under study and any other J&J medicinal product,  
Product Quality Complaint (PQC) 
Any discrete concern that questions the identity, quality, durability, reliability, safety, efficacy, 
or intended performance of a drug product. 
A complaint may allege an injury or malfunction associated with the use of the drug product.  
It may also involve the design, literature, packaging, advertising, availability, physical 
appearance or promotion of the drug product. 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered ‘‘serious’’ if, in the view of 
either the Institution or principle investigator, it results in any of the following outcomes:  
 
Death,  
 
A life-threatening adverse event,  
o Life-threatening adverse event or life-threatening suspected adverse reaction.  
 
An adverse event or suspected adverse reaction is considered ‘‘life-
threatening’’ if, in the view of the principle investigator, its 
occurrence places the patient or subject at immediate risk of death.  It 
does not include an adverse event or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death. 

 
38
 
Inpatient hospitalization or prolongation of existing hospitalization,  
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
 
A congenital anomaly/birth defect.  
 
Is a suspected transmission of infectious agents by a medicinal product 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Special Reporting Situations  
When a report contains a Johnson &Johnson medicinal product, an identifiable patient, and 
identifiable reporter, the following events represent Special Reporting Situations: 
 
overdose of Johnson & Johnson medicinal product  
 
pregnancy exposure (maternal and paternal) 
 
exposure to a medicinal product from breastfeeding  
 
suspected abuse/misuse of a medicinal Johnson & Johnson product 
 
inadvertent or accidental exposure to a medicinal Johnson & Johnson product 
 
medication error involving a medicinal Johnson & Johnson product (with or without 
patient exposure to the medicinal Johnson & Johnson product, e.g., name confusion) 
 
suspected transmission of any infectious agent via a medicinal product. 
 
Any failure of expected pharmacological action (i.e. lack of effect) of a Johnson & 
Johnson medicinal product 
 
Unexpected therapeutic or clinical benefit from use of a Johnson & Johnson medicinal 
product 
12.2 
Management of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
In general, the study clinical staff must immediately report to Janssen Scientific Affairs any serious 
adverse event and Special Reporting Situations, whether or not considered drug related.  Study 
endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in accordance 
with the protocol unless there is evidence suggesting a causal relationship between the drug and the 
event (e.g., death as a result of anaphylactic reaction or fatal hepatic necrosis).  In that case, the 
investigator must immediately report the event to Janssen Scientific Affairs.  All other non-serious 
adverse events must be reported to Janssen Scientific Affairs according to the timetable for reporting 
as specified either in the protocol or to fulfill regulatory reporting requirements. 
 
For each subject, AEs, SAEs, and Special Reporting Situations should be recorded after informed 
consent is obtained until the subject has completed participation in the study as follows: 

 
39
A Serious Adverse event or Special Reporting Situations must be reported if it occurs during 
a subject’s participation in the Study (whether receiving Study Product or not) and within 30 
days of receiving the last dose of Study Product. 
 
Any serious adverse event or Special Reporting Situations that is ongoing when a subject 
completes his/her participation in the Study must be followed until any of the following 
occurs: 
 
the event resolves or stabilizes; 
 
the event returns to baseline condition or value (if a baseline value is available); 
 
the event can be attributed to agents(s) other than the Study Product, or to factors unrelated 
to Study conduct. 
 
12.3 
Recording of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
Recording should be done in a concise manner using standard, acceptable medical terms. 
The adverse event recorded should not be a procedure or a clinical measurement (i.e. a laboratory 
value or vital sign) but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. 
Preexisting conditions that worsen in severity or frequency during the Study should also be recorded 
(a preexisting condition that does not worsen is not an adverse event). 
 
Further, a procedure or surgery is not an adverse event; rather, the event leading to the procedure or 
surgery is considered an adverse event.  Any event requiring in-patient hospitalization that occurs 
during the course of a subject’s participation in a trial must be reported as an SAE.  Hospitalizations 
that do not meet the criteria for SAE reporting are a planned surgery or procedure prior to entry into 
the study or not related to study drug.   
 
If, in the PI's judgment, a clinical significant worsening from baseline is observed in any laboratory or 
other test parameter (e.g. electrocardiogram (ECG), angiogram), physical exam finding, or vital sign, 
a corresponding clinical adverse event should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded as the 
adverse event whenever possible.  However, a complete description of the signs, symptoms and 
investigations that led to the diagnosis should be provided.  For example, if clinically significant 
elevations of liver function tests are known to be secondary to hepatitis, “hepatitis” and not “elevated 
liver function tests” should be recorded.  If the cause is not known, the abnormal test or finding should 
be recorded as an adverse event, using appropriate medical terminology (e/g/ thrombocytopenia, 
peripheral edema, QT prolongation). 
12.4 
Maintenance of Safety Information 
Safety information will be maintained in a clinical database/repository in a retrievable format.  At a 
minimum, at the end of the treatment phase (=”last patient off treatment”) as well as the end of the 
follow-up phase (=”last patient out”) of the Study, the Principal Investigator shall provide all adverse 
events, both serious and non-serious, in report format.  However, in certain circumstances more 
frequent review of the safety data may be necessary, e/g/ to fulfill a regulatory request, and as such the 
data shall be made available within a reasonable timeframe at Janssen Service’s request. 

 
40
12.5 
Reporting Timelines 
All safety information covered in Exhibit B (SAEs, Adverse Events of Special Interest, Special 
Reporting Situations, and PQCs) should be reported within 24 hours of becoming aware of the 
event(s).  
All non-serious AEs should be reported according to the timeframe outlined in the Research Funding 
Agreement section entitled Reporting of Data. 
12.6 
Transmission Methods: 
SAEs should be recorded on the Medwatch form and sent to JANSSEN SCIENTIFIC AFFAIRS, LLC, 
SAE 
Secure! 
email 
address: 
IIS-BIO/VIRO-GCO 
Central 
Email. 
RA-OMPUS-
COBS_Cen_E@its.jnj.com 
The subject line for Initial SAE Reports should be named: Lam  MD_Pt <No> Secure! SAE 
Initial Report 
The subject line for Follow Up SAE Reports should be named: Lam MD_Pt <No> Secure! 
SAE Follow up Report. 
12.7 
Procedures for Reporting Adverse Events (AE), Serious Adverse Events (SAE), 
Special Reporting Situation, and Product Quality Complaints (PQCs) to Janssen 
Scientific Affairs. 
12.7.1 
Serious Adverse Events (SAE), Adverse Events of Special Interest, and Special 
Reporting Situations 
The principle investigator will transmit these reports in a form to be provided (or a form substantially 
similar to the form provided and approved for use by Janssen Scientific Affairs in writing) in 
accordance with Section 12.6, in English within 24 hours of becoming aware of the event(s) along 
with their determination of whether the event was caused by a J&J product. 
All available clinical information relevant to the evaluation of an SAE, Adverse Events of Special 
Interest, and Special Reporting Situations including pregnancy reports (with or without an AE) 
including paternal exposure are required. 
 
The Principal Investigator is responsible for ensuring that these cases from clinical studies are 
complete and if not are promptly followed-up.  This includes ensuring the reports are fully 
investigated and thoroughly documented by the Principal Investigator and that follow-up 
information is summarized e.g. hospital records, coroner’s reports, autopsy results and recorded 
on the appropriate forms. 
 
A study case is not considered complete until all clinical details needed to interpret the case are 
received and the event has resolved, or otherwise explained, or the patient is lost to follow-up.  
Reporting of follow-up information should follow the same timeline as initial reports. 
 
Copies of any and all relevant correspondences with regulatory authorities and ethics committees 
regarding any and all serious adverse events, irrespective of association with the Study Drug in 
the course of the Study, by facsimile within 24 hours of such report or correspondence being sent 
to applicable health authorities. 
12.7.2 
Product Quality Complaints 
Any PQC, with or without an AE, (including reports of suspicion of counterfeiting, diversion, or 
tampering, and suspected transmission of pathogens) will be transmitted by the Principal Investigator 

 
41
in the form provided by Janssen Scientific Affairs in accordance with Section 12.6, in English, within 
24 hours of becoming aware of the event(s). 
12.7.3 
Reconciliation of SAEs 
At a minimum, on a quarterly basis and at the end of the Study, Janssen Scientific Affairs will provide 
to the Principal Investigator, a listing of all SAEs reported to Janssen Scientific Affairs.  The PI will 
review this listing and provide any discrepancies to Janssen Scientific Affairs. 
Upon request, the Principal Investigator shall provide Janssen Scientific Affairs with a summary list 
of all SAEs, and AEs of Special Interest and Special Reporting Situation reports to date, for 
reconciliation purposes. 
 
12.8 
Reporting of Serious Adverse Events to the FDA 
Investigators and other site personnel must inform Janssen Scientific Affairsvia a MedWatch 
form, of any serious or unexpected adverse events that occur from the time of informed 
consent from the time of consent through 30 days after administration of the last dose of study 
drug. A copy of the MedWatch report will be faxed to Janssen Scientific Affairs.  Because 
this study has an FDA IND exemption, all reportable events fall under the voluntary reporting 
requirements. Janssen Scientific Affairs will decide if it is reportable under the post-marketing 
regulations. Janssen Scientific Affairs is then required to submit postmarketing expedited 
safety reports to the FDA. 
A cover page should accompany the MedWatch form indicating: 
 Investigator’s name and address 
 The trial name/title and reference number 
The site must also indicate the causality of events in relation to all study medications as determined 
by the principal investigator. 
12.9 
Dissemination of Safety Information from Janssen Scientific Affairs to Principal 
Investigator 
Janssen Scientific Affairs will provide to the Principal Investigator IND safety reports/SUSAR 
(Serious Unexpected Suspect Adverse Reaction) reports generated by the Janssen Scientific Affairs 
for the Study Product as they become available until all subjects in the Protocol have completed their 
last Study visit according to the Protocol  (i.e. Last Subject Last Visit has occurred). 
12.10 
Monitoring of Adverse Events and Period of Observation 
AEs, both non-serious and serious (which include all deaths), will be monitored throughout the study 
as follows: 
 
AEs will be reported from the time of consent through 30 days after administration of the last 
dose of study drug and recorded.   
 
Serious pretreatment events will be reported to Janssen from the time of the signing of the ICF 
up to first dose of study drug. 
 
SAEs will be reported to Janssen Scientific Affairs from the time of consent through 30 days 
after administration of the last dose of study drug and recorded.  All SAEs should be monitored 
until they are resolved or are clearly determined to be due to a patient’s stable or chronic 
condition or intercurrent illness(es).  If an SAE occurs in the follow-up period and is thought 
to be possibly related to study drug, it must be reported.  

 
42
12.11    Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a female partner of a male patient becomes pregnant during the male patient’s participation in this 
study, the PI, or representative, must be contacted immediately.  Every effort should be made to follow 
the pregnancy for the final pregnancy outcome. 
12.12 Reconciliation of SAEs 
At a minimum, on a quarterly basis and at the end of the Study, Jansen will provide to 
the University of Colorado and/or Dr. Elaine Lam, a listing of all SAEs reported to the 
Janssen Scientific Affairs.  Janssen Scientific Affairs and/or Dr. Elaine Lam will review 
this listing and provide any discrepancies to Janssen Scientific Affairs. 
Upon request, the University of Colorado and Dr. Elaine Lam shall provide Janssen 
Scientific Affairs with a summary list of all SAEs, and AEs of Special Interest and 
Special Reporting Situation reports to date, for reconciliation purposes. 
 
13.    
ADMINISTRATIVE REQUIREMENTS 
This is an investigator-initiated trial and thus major trial decisions and document design will occur 
with the PI and supporting institution, the University of Colorado Cancer Center.  Janssen Scientific 
Affairs is providing study support and thus will have access to trial data and patient safety information. 
13.1 
Data Quality Assurance 
The investigator is required to prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each study patient.  Study monitors 
will discuss instances of missing or uninterpretable data with the investigator for resolution.  Any 
changes to study data will be monitored via an audit trail. 
13.2   
Study Monitoring 
Monitoring and Oversight 
 
The Principal Investigator (PI) will be responsible for monitoring the trial per the trial 
monitoring plan, in addition to overseeing the safety and efficacy of the trial, executing the 
DSM plan, and complying with all reporting requirements to local and federal authorities. 
This oversight will be accomplished through additional oversight from the Data and Safety 
Monitoring Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer 
Center).  The DSMC is responsible for ensuring data quality and patient safety for all 
clinical studies at the CU Cancer Center.   A summary of the DSMC’s activities is as 
follows: 
 Conduct of internal audits 
 Ongoing review of all serious adverse events (SAEs), unanticipated problems (UAPs) 
and reportable adverse events (AEs)  
 Has the authority to close and/or suspend trials for safety or trial conduct issues 
 May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs, UAPs and reportable AEs are 

 
43
reported to the DSMC, IRB and the sponsor per study protocol.  All SAEs, UAPs and 
reportable AEs are to be reported to the DSMC within 5 business days of receiving 
notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the Investigators and Clinical 
Research Coordinators (CRCs) at regularly scheduled disease-oriented working group 
meetings.  Data regarding number of subjects, significant toxicities, dose modifications, and 
treatment responses will be discussed and documented in the meeting’s minutes. 
 
The PI will provide a DSM report to the CU Cancer Center DSMC on a six-month basis. The 
DSM report will include a protocol summary; current enrollment numbers; summary of 
toxicity data to include specific SAEs, UAPs and AEs; any dose modifications; all protocol 
deviations; and protocol amendments. The DSM report to the DSMC will also include, if 
applicable, the results of any efficacy data analysis conducted, as well as any internal DSMB 
reports. Results and recommendations from the review of this six-month report by the DSMC 
will then need to be submitted by the site to the IRB of record at the time of continuing review. 
 
Janssen Scientific Affairs will not be monitoring this study. 
13.3    
Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirement(s) and will adhere 
to GCP standards.  The IRB/IEC will review all appropriate study documentation to safeguard the 
rights, safety, and well being of the patients.  The protocol, IB, ICF, advertisements (if applicable), 
written information given to the patients (including diary cards), safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB/IEC by the investigator, as 
allowed by local regulations. 
13.4    
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either the 
patient or his/her guardian or legal representative before study participation.  The method of obtaining 
and documenting the informed consent and the contents of the consent must comply with the ICH-
GCP and all applicable regulatory requirements. 
13.5    
Patient Confidentiality 
To maintain patient privacy, study drug accountability records, study reports, and communications 
will identify the patient by initials where permitted and/or by the assigned patient number.  The 
patient’s confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations. 
13.6    
Investigator Compliance 
Changes to the protocol will require written IRB/IEC approval/favorable opinion before 
implementation, except when the modification is needed to eliminate an immediate hazard or hazards 
to patients.  When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Janssen Scientific Affairs, or a designee, if 
circumstances permit, to discuss the planned course of action.  Any departures from the protocol must 
be documented. 

 
44
13.7    
On-site Audits 
Regulatory authorities, the IEC/IRB, and/or Janssen Scientific Affairs may request access to all source 
documents, and any study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times for these 
activities. 
13.8    
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at the trial site is the responsibility of the investigator.  Please see 
section 8.4.3 for details. 
All material containing study drug will be treated and disposed of in accordance with governing 
regulations. 
13.9    
Closure of the Study 
Study participation may be prematurely terminated if, in the opinion of the investigator or Janssen 
Scientific Affairs, there is sufficient reasonable cause.  Written notification documenting the reason 
for study termination will be provided by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to patients 
 
Failure to enter patients at an acceptable rate 
 
Insufficient adherence to protocol requirements 
 
Insufficient, incomplete, and/or unevaluable data 
13.10 
Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable regulatory 
requirement(s).  Records will be retained for at least 3 years after the last patient is removed from trial 
or according to applicable regulatory requirement(s).  If the investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person willing to accept 
the responsibility.   
14.    
USE OF INFORMATION 
The information obtained from the clinical study will be used toward the development of cabazitaxel 
in combination with abiraterone acetate and may be disclosed to regulatory authorities, other 
investigators, corporate partners, or consultants as required.  Additionally, Janssen Scientific Affairs 
will also have access to complete data obtained during the study as the provider of an investigational 
agent. 
Upon completion of the clinical study and evaluation of results by the hospital or institution and/or 
investigator may publish or disclose the clinical trial results pursuant to the terms contained in the 
applicable Clinical Trial Agreement. 
 
 
Printed Name of Investigator 
 
_____________________________________ 
 
___________________________________ 

 
45
Signature of Investigator 
 
 
 
Date 
 

 
46
15.    
REFERENCES 
1. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012 
Jan-Feb;62(1):10-29. 
2. 
Sonpavde G. Abiraterone and increased survival in metastatic prostate cancer. N Engl 
J Med. 2011 Aug 25;365(8):766-7; author reply 7-8. 
3. 
Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr., Jones JA, Taplin ME, et al. 
Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced 
refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. 
4. 
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus 
prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 
Oct 7;351(15):1502-12. 
5. 
Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et 
al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in 
patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006 
Jul 1;24(19):3089-94. 
6. 
Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 
2004 Apr;4(4):253-65. 
7. 
Gan L, Chen S, Wang Y, Watahiki A, Bohrer L, Sun Z, et al. Inhibition of the androgen 
receptor as a novel mechanism of taxol chemotherapy in prostate cancer. Cancer Res. 2009 
Nov 1;69(21):8386-94. 
8. 
Jiang J, Huang H. Targeting the Androgen Receptor by Taxol in Castration-Resistant 
Prostate Cancer. Mol Cell Pharmacol. 2010 Jan 1;2(1):1-5. 
9. 
de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. 
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer 
progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 
2;376(9747):1147-54. 
10. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/201023lbl.pdf SpJFpiAa. 
11. 
Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical 
trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant 
prostate cancer commonly remains hormone driven. J Clin Oncol. 2008 Oct 1;26(28):4563-
71. 
12. 
Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW. Effects of novel 
17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis 
in vitro and in vivo. J Steroid Biochem Mol Biol. 2003 Apr;84(5):555-62. 
13. 
Ryan CJ, Smith MR, Fong L, Rosenberg JE, Kantoff P, Raynaud F, et al. Phase I 
clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in 
patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J 
Clin Oncol. 2010 Mar 20;28(9):1481-8. 

 
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14. 
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and 
increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-
2005. 
15. 
Ryan CJ, Smith R, de Bono J, Molina A, Logothetis CJ, De Souza P, et al. Interim 
analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate 
(AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer 
(mCRPC). J Clin Oncol. 2012(30):suppl Abstr LBA4518. 
16. 
Rathkopf DE, Smith MR, de Bono JS, Logothetis CJ, Shore ND, de Souza P, et al. 
Updated Interim Efficacy Analysis and Long-term Safety of Abiraterone Acetate in Metastatic 
Castration-resistant Prostate Cancer Patients Without Prior Chemotherapy (COU-AA-302). 
Eur Urol. 2014 Mar 6. 
17. 
Zytiga (abiraterone acetate) Prescribing Information. 2013 9/2013. 
18. 
Mostaghel EA, Nelson P, Lange PH, Lin DW, Taplin M, Balk SP, et al. Neoadjuvant 
androgen pathway suppression prior to prostatectomy. J Clin Oncol. 2012;30:suppl, abstr 
4520. 
19. 
Pinto-Bazurco Mendieta MA, Negri M, Jagusch C, Muller-Vieira U, Lauterbach T, 
Hartmann RW. Synthesis, biological evaluation, and molecular modeling of abiraterone 
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Aug 28;51(16):5009-18. 
20. 
Jevtana (Cabazitaxel) Prescribing Information. In: LLC s-aUS, editor.2010. 
21. 
Massard C, Pezaro C, Bobilev D, Omlin AG, Bianchini D, Estelles DL, et al. A phase 
I/II study of cabazitaxel (Cbz) combined with abiraterone acetate (AA) and prednisone (P) in 
patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) whose disease has 
progressed after docetaxel (D) chemotherapy: Preliminary results. J Clin Oncol. 2013;31(abstr 
5049). 
 
22.  
Mateo J, Fizazi K, Pezaro CJ, Loriot Y, Mehra N, Albiges L, et al.  Phase 1/2 trial of 
cabazitaxel with abiraterone acetate in patients with metastatic castration-resistant prostate 
cancer (mCRPC) progressing after docetaxel and abiraterone acetate: Phase 2 results.  J Clin 
Oncol 33, 2015 (suppl 7; abstr 268). 
 
23.  
Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al.  
Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.  N Engl J Med 
2015, published on August 5, 2015, at NEJM.org; DOI: 10.1056/NEJMoa1503747. 
24. 
Common Terminology Criteria for Adverse Events (CTCAE). 2010. 
 

 
48
16.    
APPENDICES 
16.1    
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work) 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry 
out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair 
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-
55.(28)