Phase II, Randomized, Open-label, Multicenter Study in Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Who Have PRIMary Resistance to Abiraterone Acetate or Enzalutamide Treatment Comparing the Anti-tumor Effect of CABazitaxel to Alternative Androgen Receptors (AR) Targeted Therapy
Phase: PHASE2
Conditions: Prostate Cancer Metastatic
Sponsor: Sanofi



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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
(electronic 
 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: XRP6258 
Jevtana®/cabazitaxel 
STUDY No: XRP6258-LPS14022  
STUDY NAME: PRIMCAB 
TITLE 
Phase II, randomized, open label, multicenter study in chemotherapy-naïve 
metastatic Castration-Resistant Prostate Cancer (mCRPC) patients who have 
PRIMary resistance to abiraterone acetate or Enzalutamide treatment 
comparing the anti-tumor effect of CABazitaxel to alternative Androgen 
Receptors (AR) targeted therapy 
INVESTIGATOR/TRIAL LOCATION 
Multicenter/ International 
PHASE OF DEVELOPMENT 
Phase II 
STUDY OBJECTIVE(S) 
 
Primary objective 
To demonstrate the superiority in term of radiographic Progression-Free 
Survival (rPFS) [using Response Evaluation Criteria In Solid Tumors 
(RECIST) 1.1 and PCWG2] (1)(2) of cabazitaxel at 25 mg/m² plus prednisone 
(Arm A) versus either enzalutamide at 160 mg once daily or abiraterone 
acetate at 1000 mg once daily plus prednisone (Arm B) in chemotherapy-
naïve patients with metastatic Castration-Resistant Prostate Cancer 
(mCRPC) who have disease progression while receiving  AR targeted therapy 
(abiraterone plus prednisone or enzalutamide) within 12 months of treatment 
initiation (12 months). 
 
Secondary objectives  
x 
To compare efficacy of  cabazitaxel plus prednisone to 
enzalutamide or abiraterone acetate plus prednisone for: 
- 
PSA response rate, 
- 
Progression Free Survival (PFS),  
- 
Overall Survival (OS), 
- 
Time To PSA Progression (TTPP),  
- 
Tumor response rate in patients with measurable disease 
(RECIST 1.1), 
- 
Duration of tumor response, 
- 
Pain response, 
- 
Time To Pain Progression,  
- 
Symptomatic skeletal events  (SSE) rate, 
- 
Time to occurrence of any symptomatic skeletal events (SSE) 
x 
To analyze messenger RNAs including androgen-receptor splice 
variant 7 messenger RNA (AR-V7) at baseline and post-treatment 
in Circulating Tumor Cells (CTCs). 
x 
To evaluate safety in the 2 treatment arms 
 
 
x 
To analyze Circulating Tumor Cells (CTCs) phenotypes as well as 
expression and localization of proteins including androgen receptors 
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(AR) isoforms in CTCs at baseline.  
x 
To collect circulating free nucleic acids (cfDNA and cfRNA) derived 
from plasma at baseline, on treatment and post-treatment for 
biomarker studies. 
x 
To collect germline DNA derived from whole blood at baseline for 
biomarker studies and subtractive mutation analysis. 
 
STUDY DESIGN 
This is a prospective, multicenter, multinational, randomized, open label 
study, comparing the efficacy of cabazitaxel at 25 mg/m² plus prednisone 
(Arm A) versus either enzalutamide at 160 mg once daily or abiraterone 
acetate at 1000 mg once daily plus prednisone (Arm B) in term of rPFS [using 
RECIST 1.1] in chemotherapy-naïve patients with mCRPC who have primary 
resistance to abiraterone acetate or enzalutamide. 
Resistant population is defined as patients who have disease progression 
while receiving AR targeted therapy within 12 months of AR treatment 
initiation (12 months) (3) 
Each patient will be treated until disease progression, unacceptable toxicity, 
or patient’s refusal of further study treatment.  
A Steering Committee will be responsible for supervising the progress of the 
trial. This committee will include the 3 Study Chairmen’s and Sponsor’s 
representatives. 
Treatment allocation will be performed by an Interactive Voice/Web Response 
System (IVRS/IWRS). All eligible patients will be randomly assigned to either 
arm A or B in a 1:1 proportion. 
Randomization will be stratified by: extra nodal visceral metastases (yes, no), 
level of PSA decline within 12 months of initiation of AR targeted therapy (no 
decline, decline 1% to <50%, decline 50%) and time from AR targeted agent 
initiation to progression ([0 ; 6 months], ]6 ; 12 months]. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria  
I 01. 
Diagnosis of histologically or cytologically confirmed prostate 
adenocarcinoma. 
I 02. 
Metastatic disease. 
I 03. 
Progressive disease (PD) while receiving AR targeted therapy with 
abiraterone acetate or enzalutamide within 12 months of treatment 
initiation (12 months) by at least one of the following:  
a) 
Progression in measurable disease (RECIST 1.1 criteria). 
Patient with measurable disease must have at least one lesion 
that can be accurately measured in at least one dimension 
(longest diameter to be recorded). Each lesion must be at least 
10 mm when measured by computed tomography (CT) [CT 
scan thickness no greater than 5 mm] or magnetic resonance 
imaging (MRI). Lymph nodes should be 15 mm in short axis. 
As defined by PCWG2 (2), if lymph node metastasis is the only 
evidence of metastasis, it must be 20 mm in diameter when 
measured by spiral CT or MRI. Previously irradiated lesions, 
primary prostate lesion and bone lesions will be considered 
non-measurable disease, and/or 
b) 
Appearance of 2 or more new bone lesions. They must be 
confirmed by other imaging modalities (CT; MRI)  if ambiguous 
(electronic 
 
 
 
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results (PCWG2) , and/or 
c) 
Rising PSA defined (PCWG2) as at least two consecutive rises 
in PSA to be documented over a reference value (measure 1) 
taken at least one week apart. The first rising PSA (measure 2) 
should be taken at least 7 days after the reference value. A 
third confirmatory PSA measure is required (2nd beyond the 
reference level) to be greater than the second measure and it 
must be obtained at least 7 days after the 2nd measure. If this 
is not the case, a fourth PSA measure is required to be taken 
and be greater than the 2nd measure. The third (or the fourth) 
confirmatory PSA should be taken within 4 weeks prior to 
randomization (Appendix A). In case of progression based on 
rising PSA only, the first rising PSA (measure 2) must be 
obtained within 6 months of initiation of AR targeted therapy 
(6 months). 
Duration of the first AR targeted agent treatment should not exceed 
12 months for patients with PD within 6 months and should not 
exceed 18 months for those with PD between 6 and 12 months. 
I 04. 
A PSA value of at least 2 ng/mL is required at study entry. 
I 05. 
Effective castration (serum testosterone levels <0.5 ng/mL).  
I 06. 
Prior AR targeted therapy (abiraterone acetate or enzalutamide) must 
be stopped at least 2 weeks before study treatment.  
I 07. 
Signed written informed consent. 
Exclusion criteria 
Related to methodology: 
E 01. Prior chemotherapy for prostate cancer, except estramustine and 
except adjuvant/neoadjuvant treatment completed >3 years ago. No 
further anti-cancer therapy after the previous AR targeted therapy and 
before inclusion. Prior docetaxel in hormone sensitive setting is 
allowed if completed >1 year before randomization (4). Prior 
immunotherapy is allowed. 
E 02. Less than 28 days elapsed from prior treatment with immunotherapy, 
radiotherapy or surgery to the time of randomization.  
E 03. Adverse events (excluding alopecia and those listed in the specific 
exclusion criteria) from any prior anticancer therapy of grade >1 
(National Cancer Institute Common Terminology Criteria 
[NCI CTCAE] v4.0) at the time of randomization. 
E 04. Less than 18 years (or country’s legal age of majority if the legal age 
is >18 years). 
E 05. Eastern Cooperative Oncology Group (ECOG) performance status 
>1. 
E 06. History of brain metastases, uncontrolled spinal cord compression, or 
carcinomatous meningitis or new evidence of brain or leptomeningeal 
disease. 
E 07. Prior malignancy. Adequately treated basal cell or squamous cell skin 
or superficial (pTis, pTa, and pT1) bladder cancer are allowed, as well 
as any other cancer for which treatment has been completed 
5 years ago and from which the patient has been disease-free for 
(electronic 
 
 
 
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5 years.  
E 08. Participation in another clinical trial and any concurrent treatment with 
any investigational drug within 30 days prior to randomization. 
E 09. Acquired immunodeficiency syndrome (AIDS-related illnesses) or 
known HIV disease requiring antiretroviral treatment. 
E 10. Any severe acute or chronic medical condition including uncontrolled 
diabetes mellitus, severe renal impairment, history of cardiovascular 
disease (uncontrolled hypertension, arterial thrombotic events in the 
past 6 months, congestive heart failure, severe or unstable angina 
pectoris, recent myocardial infraction within last 6 months or 
uncontrolled cardiac arrhythmia), which could impair the ability of the 
patient to participate to the study or interfere with interpretation of 
study results, or patient unable to comply with the study procedures. 
E 11. Patients with reproductive potential who do not agree to use accepted 
and effective method of contraception during the study treatment 
period and up to 6 months after the last administered dose. The 
definition of “effective method of contraception” will be based on the 
investigator’s judgment 
Related to study treatment: 
E 12. Known allergies, hypersensitivity or intolerance to prednisone or 
excipients of abiraterone acetate or enzalutamide. History of 
hypersensitivity to docetaxel or polysorbate 80. 
E 13. Known history of mineralocorticoid excess or deficiency (not 
applicable to patients who have already been treated with abiraterone 
acetate in first line before inclusion). 
E 14. History of seizure, underlying brain injury with loss of consciousness, 
transient ischemic attack within the past 12 months, cerebral vascular 
accident, brain arteriovenous malformation or the use of concomitant 
medications that may lower the seizure threshold (not applicable to 
patients who have already been treated with enzalutamide in first line 
before inclusion). 
E 15. Unable to swallow a whole tablet or capsule 
E 16. Inadequate organ and bone marrow function as evidenced by: 
a) 
Hemoglobin <10.0 g/dL 
b) 
Absolute neutrophil count <1.5 x 109/L 
c) 
Platelet count <100 x 109/L  
d) 
AST/SGOT and/or ALT/SGPT >1.5 x ULN; 
e) 
Total bilirubin >1.0 x ULN 
f) 
Potassium <3.5 mmol/L 
g) 
Serum albumin <3.0 g/dL 
h) 
Child-Pugh Class B and C 
E 17. Contraindications to the use of corticosteroid treatment. 
E 18. Symptomatic peripheral neuropathy grade 2 (National Cancer 
Institute Common Terminology Criteria for Adverse 
Events [NCI CTCAE] v.4.0). 
E 19. Concomitant vaccination with yellow fever vaccine. 
(electronic 
 
 
 
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Total expected number of patients 
Approximately 206 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
 
 
Formulation 
Arm A: 
Cabazitaxel (XRP6258) 
Cabazitaxel is supplied as a sterile, non-pyrogenic, non-aqueous yellowish to 
brownish yellow solution contained in a 15 mL clear glass vial, stoppered with 
a chlorobutyl rubber closure coated with a transparent ETFE coating. The 
rubber closure is crimped to the vial with an aluminum cap covered with a 
light green plastic flip-off cap.  
Single-dose vial, containing a total of 60 mg of cabazitaxel expressed as 
anhydrous and solvent-free basis, per 1.5 mL of solution. The fill volume has 
been established to include an overfill, (ie, 1.5 mL [nominal volume] + 
0.33 mL). This overfill was determined to ensure that a 10 mg/mL 
concentration is obtained in the premix and that 60 mg dose can be extracted 
Solvent:  
The diluent used for the preparation of the premix is a sterile, non pyrogenic 
solution containing a 13% w/w ethanol solution in water for injection. This 
solution is contained in a 15 mL clear glass vial, stoppered with a chlorobutyl 
rubber closure coated with a transparent ETFE coating. The rubber closure is 
crimped to the vial with either an aluminum cap covered with a light grey 
plastic flip-off cap or a gold-color aluminum cap covered with a clear plastic 
flip-off cap. 
Each vial of solvent is overfilled to ensure that a 10 mg/mL concentration is 
obtained in the Premix and that 60 mg dose can be extracted. (ie, 4.5 mL 
(nominal volume) + 1.17 mL]. 
Each vial of cabazitaxel must be diluted with the ENTIRE content of one 
solvent vial. 
The solution is a clear colorless liquid. 
 
Arm B: 
Abiraterone acetate OR Enzalutamide 
Abiraterone acetate 250 mg tablets, white to off-white, oval tablets debossed 
with AA250 on one side. Abiraterone acetate 250 mg tablets are available in 
high-density polyethylene bottles of 120 tablets. 
OR 
Enzalutamide 40 mg capsules, white to off-white oblong soft capsules 
(approximately 20 mm x 9 mm) imprinted with “ENZ” in black ink on one side. 
Commercially available formulations will be used for the comparators 
(abiraterone acetate and enzalutamide). 
Route(s) of administration 
Cabazitaxel will be administered by IV route.   
Abiraterone acetate and enzalutamide will be administered by oral route 
Dose regimen 
Arm A: 
Cabazitaxel 25 mg/m² intravenously in 1 hour (Day 1) every 3 weeks, plus 
prednisone 10 mg orally given daily. A cycle is defined as a 3-weeks period 
(electronic 
 
 
 
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Arm B: 
Abiraterone acetate: Patients who were treated with enzalutamide before 
study entry, will receive abiraterone acetate at the dose of 1000 mg (4 tablets) 
orally (PO) continuously once daily from D1 to D21. It must be taken on an 
empty stomach. No food should be consumed for at least 2 hours before the 
dose is taken and at least 1 hour after the dose is taken. The tablets should 
be swallowed whole with water, plus prednisone 5 mg orally twice daily. A 
cycle is defined as a 3-weeks period.  
OR 
Enzalutamide: Patients who were treated with abiraterone acetate before 
study entry, will receive enzalutamide at the dose of 160 mg (4 capsules) 
orally (PO) continuously once daily from D1 to D21, with or without food, 
capsules should be swallowed whole. A cycle is defined as a 3-weeks period 
Non-Investigational medicinal 
product(s) (IMP) 
Prednisone or Prednisolone: 
Commercially available product will be used.  
Prednisone or Prednisolone will be administered by oral route. 
ENDPOINT(S) 
 
Primary endpoint 
Radiographic Progression-Free Survival (rPFS) defined as the time from 
randomization to the occurrence of one of the following: 
x 
Radiological tumor progressions using RECIST 1.1 
x 
Progression of  bone lesions using PCWG2 criteria  
x 
Death due to any cause 
 
Secondary endpoint(s) 
Efficacy 
x 
PSA response defined as a reduction from baseline PSA level of at 
least 50%, maintained for at least 3 weeks.  
x 
Progression-free survival defined as the time interval between the 
date of randomization and the date of the first documentation of any 
of the following events (1)(2) :  
x 
Radiological tumor progression by RECIST 1.1 and PCWG2, 
x 
PSA progression, 
x 
Pain progression, 
x 
Death due to any cause. 
x 
Overall Survival defined as the time interval from the date of 
randomization to the date of death due to any cause 
x 
Time to PSA progression (TTPP) defined as the time interval 
between the date of randomization and the date of first documented 
PSA progression. PSA progression is defined as (2)(Appendix A):  
x 
Decline from baseline: an increase of 25% (at least 
2ng/mL) over the nadir value, confirmed by a second PSA 
value at least 3 weeks apart. 
x 
No decline from baseline: an increase of 25% (at least 
2ng/mL) over the baseline value after 12 weeks of treatment, 
confirmed by a second PSA value at least 3 weeks apart. 
(electronic 
 
 
 
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Early increase in PSA within 12 weeks, when followed by subsequent decline, 
is ignored in determining this endpoint. 
x 
Tumor response in patients with measurable disease (RECIST 
1.1). 
x 
Duration of tumor response in patients with measurable disease, 
defined as the time between the first evaluation at which the tumor 
response criteria are met and the first documentation of tumor 
progression. 
x 
Pain response defined as a decrease by <30% from baseline in 
the average of Brief Pain Inventory-Short Form (BPI-SF) pain 
intensity score observed at 2 consecutive evaluations 3 weeks 
apart without increase in analgesic usage score (defined as a 1 
point increase on the WHO analgesic scale). 
x 
Time to Pain progression defined as the time interval between the 
date of randomization and the date of the first documented pain 
progression. Pain Progression will be defined as increase by 30% 
from baseline in the average of BPI-SF pain intensity observed at 
2 consecutive evaluations 3 weeks apart without decrease in 
analgesic usage score OR increase in analgesic usage score of 
30% or greater. 
Early increase in BPI-SF or analgesic usage within 12 weeks, when followed 
by subsequent decline, is ignored in determining this endpoint.  
x 
Symptomatic Skeletal Events (SSE) rate, occurrence of SSE (by 
clinical evaluation) is defined (5) as: 
x 
The occurrence of a new symptomatic pathological fracture, or 
x 
The use of external beam radiation to relieve bone pain, or 
x 
The occurrence of spinal cord compression, or  
x 
Tumor-related orthopeadic surgical intervention 
x 
Time to occurrence of SSE defined as the time interval between 
the date of randomization and the date of the occurrence of the first 
event defining a SSE, whichever is earlier. 
x 
Analysis of messenger RNAs including androgen-receptor splice 
variant 7 messenger RNA (AR-V7) at baseline and post-treatment 
in Circulating Tumor Cells (CTCs).  
 
Safety: 
x 
Treatment Emergent Adverse Events (TEAE): Type according to 
MedDRA (Medical Dictionary for Regulatory Activities), frequency, 
severity according to NCI CTCAE V4.0, seriousness, and 
relationship of study treatment will be assessed. Laboratory 
abnormalities will be assessed according to the NCI CTCAE v.4.0. 
 
Biomarkers:  
x 
Analysis of Circulating Tumor Cells (CTCs) phenotypes as well as 
expression and localization of proteins including AR isoforms in 
CTCs at baseline. 
x 
Analysis of tumoral genetic and genomic variations in circulating 
free nucleic acids derived from plasma at baseline, on treatment 
and post-treatment. Subtractive mutation analysis will be performed 
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with germline DNA data to identify tumoral specific variations. 
 
ASSESSMENT SCHEDULE 
Screening will be performed within 4 weeks before randomization.  
Clinical examinations (including height at baseline only, weight, ECOG PS 
and vital signs), laboratory tests (including complete blood counts, and serum 
chemistry), concomitant medications and AEs (NCI CTCAE v.4.0) will be 
obtained prior to drug administration, every cycle before treatment 
administration and up to 30 days after the last study treatment administration. 
Weight and ECOG PS will be collected until disease progression, start of 
another anticancer therapy or study cut-off date, whichever comes first. ECG 
will be obtained within 8 days prior to first drug administration and at the end 
of treatment visit only if clinically indicated or cardiac event during the 
treatment period. 
Serum testosterone will be measured at baseline.  
PSA will be determined at baseline, every 3 weeks at each visit before study 
treatment administration, at the end of treatment visit, every 12 weeks at each 
follow-up until the end of the first further anticancer therapy if any or study 
cut-off whichever comes first. 
Patient’s diary to be used by all patients to record the consumption of 
abiraterone acetate or enzalutamide (in Arm B) and/or prednisone or 
prednisolone. 
Completion of Pain, and analgesic diary and SSE assessment will be 
obtained at baseline, every 3 weeks at each visit before study treatment 
administration, at the end of treatment visit, and then completion pain and 
analgesic scale will be done every 12 weeks at each follow-up until disease 
progression, death or study cut-off whichever comes first SSE will be 
assessed every 12 weeks until occurrence of first SSE or study cut-off, 
whichever comes first.  
Tumor radiological evaluation by computerized tomography (CT) or magnetic 
resonance imaging (MRI) of the whole body (chest, abdomen, and pelvis) and 
by bone scan for all patients at baseline, every 9 weeks for the first 6 months 
(27 weeks), then every 12 weeks until radiological tumor progression is 
documented, start of another cancer therapy or study cut-off, whichever 
comes first, using the same method for each assessment.  
Blood samples for CTCs analysis will be collected in patients at screening 
(24h apart before first cycle administration) and at relapse or EOT. 
Blood samples for cfDNA/cfRNA analysis will be collected in patients at 
screening, at C4D1 and at relapse or EOT. 
Blood samples for germline DNA collection will be done in patients at 
screening. 
After study treatment discontinuation, patients will be followed every 12 weeks 
until death, study cut-off date or withdrawal of patients’ consent. Details of any 
further anticancer-therapy will be collected 
STATISTICAL CONSIDERATIONS 
 
 
 
Based on bibliographic references (6)(7)(8)(9)(10), a Hazard Ratio of 0.67 is 
targeted as the smallest effect of clinical interest. The following table presents 
how such a Hazard Ratio (HR) translates for a variety of envisaged median 
rPFS in the abiraterone acetate or Enzalutamide group (11)(12). 
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median rPFS (month) 
Hazard Ratio 
abiraterone acetate or 
Enzalutamide group 
Cabazitaxel group 
0.67 
4 
6.0 
0.67 
5 
7.5 
0.67 
6 
9.0 
 
A total of 155 patients with event are needed to achieve 80% power to 
demonstrate rPFS superiority of Cabazitaxel over abiraterone acetate or 
Enzalutamide by one-sided log rank test at 0.05 type I error rate. Further 
assuming the accrual is at a constant rate of 4 patients per month for 5 
months and then 11 patients per month, a total of 206 patients in 2 arms (103 
patients per arm) is anticipated to be needed to reach the targeted number of 
patients with event. 
Analysis population: 
Intent-to-Treat (ITT) population: This population includes all randomized 
patients. It is the primary population for all efficacy parameters. All analyses 
using this population will be based on the treatment assigned by 
randomization. 
Safety population: This population includes all patients who will take at least 
one dose of the study drug. This population is for safety analyses. All 
analyses using this population will be based on the treatment actually 
received. 
Evaluable population: tumor response will be evaluated in patients with 
measurable disease at baseline. PSA response will be evaluated in patients 
with >10 ng/dL. Pain response will be evaluated in patients using BPI-SF and 
WHO Analgesic Ladder. 
Primary analysis: 
Primary analysis will consist of rPFS comparison between abiraterone acetate 
or enzalutamide group and Cabazitaxel group through a one-sided 5% 
log-rank adjusted for the stratification factors (extra nodal visceral 
metastases, time from AR targeted agent initiation to progression and level of 
PSA decline) as specified at the time of randomization. This analysis will be 
performed on the ITT population. If radiological progression or death is not 
observed during the study, data on rPFS will be censored at the date patient 
is known to be alive or at the cut-off date, whichever comes first. 
The estimates of the hazard ratio and corresponding 90% and 95% 
confidence interval will also be provided using Cox model adjusted for the 
stratification factors. Medians survival times and 95% confidence intervals will 
also be provided by treatment arm. The survival curves will be estimated 
using Kaplan-Meier estimates. 
Analysis of secondary endpoints: 
Time To event data will be compared between the 2 treatment arms by the 
log-rank test procedure. Medians and 95% confidence intervals will also be 
(electronic 
 
 
 
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provided by treatment arm. Hazard ratios and 95% confidence intervals will 
be provided using a Cox proportional hazard model. 
PSA response will be compared between groups using chi-square tests under 
evaluable population. 
Safety endpoints will be summarized by the frequency in patients and by 
toxicity grade. 
 
DURATION OF STUDY PERIOD (per 
patient)  
Patients will be treated until radiographic progressive disease, unacceptable 
toxicity, patient’s refusal of further study treatment. All patients will be followed 
when on study treatment and after completion of study treatment during follow 
up period until death, the study cutoff date, or withdrawal of patients’ consent 
whichever comes first. 
 
(electronic 
 
 
 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
(electronic 
 
 
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1.2 
STUDY FLOW CHART 
Evaluation 
Baseline 
Treatment period 
First cycle within 7 days after randomization 
Post- treatment follow-
up period 
 
Prior to randomization 
Every cycle 
End of treatment 
(30 days after last 
treatment) 
Every 12 weeks 
Informed Consent  
Before any study procedures 
 
 
 
Inclusion/Exclusion Criteria 
Within 8 days 
 
 
 
Patient demography 
Within 4 weeks 
 
 
 
Prior Medical/Surgical & Cancer Historya 
Within 4 weeks 
 
 
 
Physical Examinationb 
Within 8 days 
X 
X 
X (ECOG and weight only) 
Laboratory Studies c* 
Within 8 days 
X 
(Hematology/Biochemistry weekly during 
3 first cycles) 
X 
 
12 lead Electrocardiogram d* 
Within 8 days 
 
X 
 
Study drug Administration e 
 
X 
 
 
Adverse Events f 
 
X 
X 
X 
Prior/ Concomitant/ Post Medications g 
Within 4 weeks 
X 
X 
X(if indicated) 
Other investigations 
As clinically indicated 
X 
X 
X 
Skeletal Related Event h 
Within 8 days 
X 
X 
X 
Tumor Assessment i 
Within 4 weeks 
every 9  weeks  the first 6 months 
(27 weeks) then every 12 weeks 
X 
X 
Serum Testosterone Measurement j 
Within 4 weeks 
 
 
 
PSA Measurement k** 
Within 8 days 
X 
X 
X 
Analgesic & Pain l 
Within 3 days 
X 
X 
X 
Patient’s diarym 
 
X 
 
 
Circulating Tumor Cells (CTCs)n 
Within 8 days 
 
X 
 
cfDNA/cfRNA o 
Within 8 days 
D1 of cycle 4 
X 
 
Germline DNA o 
Within 8 days 
 
 
 
Further anticancer therapy p 
 
 
 
X 
Survival statusq 
 
 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N 
r 
 
 
X 
(electronic 
 
 
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Evaluation 
Baseline 
Treatment period 
First cycle within 7 days after randomization 
Post- treatment follow-
up period 
* To be repeated if performed more than 8 days before the 1st infusion. ** Must be performed prior to registration for eligibility assessment. 
a Prior Medical/Surgical & Cancer History Includes cancer diagnosis (primary tumor characteristics and metastatic sites), prior surgery for cancer, radiotherapy, systemic anticancer therapy, and concurrent illness. 
b Physical Examination: Includes examination of major body systems (height (at baseline only), body weight, ECOG PS and vital signs). During the follow-up period, ECOG PS, weight will be collected every 12 weeks from end of 
study treatment until disease progression, start of other anticancer therapy or study cut-off, whichever comes first. 
c Laboratory Studies Includes, prior each cycle, hematology (WBC with differential count, ANC, hemoglobin, platelet count). Blood biochemistry (sodium, potassium, calcium, phosphorus, blood urea nitrogen (BUN), magnesium, 
LDH, creatinine, total protein, albumin, SGOT (AST), SGPT (ALT), alkaline phosphatase, total bilirubin, glucose. In addition, hematology and biochemistry will be performed every week (D8 and D15) during the 3 first cycles and 
then within further cycles in case of fever or infection. During treatment, creatinine clearance (CLcr) should be performed if creatinine >1 x ULN. Coagulation (prothrombin time expressed as international normalized ratio) at 
baseline. In addition and only at baseline: serum Chromogranin A (CgA). 
d 12-lead ECG to be performed at baseline, and at end of study treatment only if clinically indicated or cardiac event during the treatment period. 
e Study drug Administration Arm A: Cabazitaxel 25 mg/m² will be administered on Days 1 of each 21-day cycle  +  prednisone 10 mg daily per os (in countries where prednisone is not commercially available prednisolone 10 mg 
daily per os may be used). Cycle administration will start within 7 calendar days of randomization, and then repeated every 3 weeks. Arm B: abiraterone acetate 1000 mg (4 tablets) orally once daily plus prednisone 5 mg orally 
twice daily, continuously or enzalutamide 160 mg (4 capsules) orally once daily continuously. 
f 
Adverse Events The period of safety observation starts from the time the patient gives informed consent. All adverse events will be recorded until 30 days after the last administration of study drugs. During the follow-up period, 
only ongoing related or new related adverse events will be recorded. Serious adverse events ongoing at the end of the study treatment will be followed during the follow-up period until resolution or stabilization regardless of 
relationship with study drugs. Adverse events will be recorded according to NCI-CTCAE version 4.0. 
g Prior/ Concomitant/ Post Medications Concomitant medications and treatments will be recorded from 4 weeks prior to the start of study drug, before every cycle during the study treatment period, and up to 30 days after the final 
dose of study drug. Once the patient has withdrawn from study treatment, concomitant medication should only be recorded if used to treat new or unresolved study treatment related adverse events. 
h Symptomatic Skeletal Event: The use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture, or occurrence of spinal cord compression, or tumor-related orthopeadic surgical 
intervention until the occurrence of the first SSE or study cut-off date. 
i 
Tumor Assessment Chest, abdomen, and pelvic CT-scan or MRI, bone scan and all other exams as clinically indicated (e.g. brain CT-Scan or MRI in case of clinical suspicion of central nervous system involvement) to be 
performed to assess disease status at baseline within 4 weeks prior randomization (bone scan performed within 6 weeks prior to randomization is allowed), then every 9 weeks for the first 6 months (27 weeks), then every 12 weeks 
until radiological tumor progression, whenever disease progression is suspected, using the same method for each assessment to follow all target and/ or non-target lesions present at baseline, start of another anticancer therapy or 
study cut-off, whichever comes first. In addition, bone scan  will be repeated to confirm progression (6 weeks after initial documentation of progression); In case of doubtful lesions on bone scan, bone-centered X-ray or MRI scan 
should be performed to determine the nature of those lesions (metastatic or not). In post treatment follow up period, patients that have not progressed or started another anticancer therapy, tumor assessment to be performed every 
12 weeks.  
j 
Serum testosterone measurement, to be performed at baseline only 
k PSA measurements to be performed at baseline and then repeated on pre dose of Day 1 of each cycle, approximately 30 days after the last study treatment administration (end of treatment visit), every 12 weeks during the 
follow-up period until the end of the first further anticancer therapy if any or the study cutoff date, whichever comes first.  
l 
Analgesic and pain diary information should be collected (at baseline,  and before each cycle, at the end of treatment and every 12 weeks until disease progression, start of another anticancer therapy or study cut off, whichever 
comes first. 
m Patient’s diary to be used by all patients to record the consumption of abiraterone acetate or enzalutamide (in Arm B) and/or prednisone or prednisolone.  
n Circulating Tumor Cells (CTCs) – CTCs assays will be done by 2 central laboratories. 3 samples will be taken prior randomization and 2 of them at least 24h apart before first cycle administration at screening (within 8 days during 
abiraterone acetate or enzalutamide washout) and at relapse or EOT if any other reason of discontinuation. 
o Samples for cfDNA/cfRNA/germline DNA: 3 samples will be taken prior randomization and 2 of them at least 24h apart before first cycle administration at screening (within 8 days during abiraterone acetate or enzalutamide 
washout)/at C4D1/ and at relapse or EOT if any other reason of discontinuation and stored for future exploratory biomarkers.  
p Further anticancer therapy if any will be collected after patient treatment discontinuation. 
q Survival status: During the follow-up period, patients who went off study treatment prior to documented disease progression will be evaluated for tumor progression, ECOG, weight, PS, Pain and HRQL every 12 weeks from end of 
study treatment until disease progression or start of other anticancer therapy. Further anticancer therapy data will be collected until death or study cutoff date. 
r 
Randomization All eligible patients will be randomly assigned to one of the 2 treatment groups using an Interactive Voice/Web Response System (IVRSIWRS). Study treatment should be started within 7 calendar days from 
randomization. 
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TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL 01 ..............................................................................................1 
1 
FLOW CHARTS.............................................................................................................................13 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................13 
1.2 
STUDY FLOW CHART ..................................................................................................................14 
2 
TABLE OF CONTENTS ................................................................................................................16 
3 
LIST OF ABBREVIATIONS ..........................................................................................................22 
4 
INTRODUCTION AND RATIONALE.............................................................................................24 
4.1 
INTRODUCTION............................................................................................................................24 
4.2 
INVESTIGATIONAL MEDICINAL PRODUCT ...............................................................................25 
4.2.1 
Preclinical data...............................................................................................................................25 
4.2.2 
Summary of clinical data................................................................................................................26 
4.2.2.1 
Phase 1 ..........................................................................................................................................26 
4.2.2.2 
Phase 2 ..........................................................................................................................................26 
4.2.2.3 
Phase 3 ..........................................................................................................................................27 
4.3 
STUDY RATIONALE......................................................................................................................28 
5 
STUDY OBJECTIVES ...................................................................................................................32 
5.1 
PRIMARY.......................................................................................................................................32 
5.2 
SECONDARY ................................................................................................................................32 
5.3 
EXPLORATORY ............................................................................................................................32 
6 
STUDY DESIGN ............................................................................................................................33 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................33 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................33 
6.2.1 
Duration of study participation for each patient .............................................................................33 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................34 
6.3 
INTERIM ANALYSIS......................................................................................................................34 
6.4 
STUDY COMMITTEES..................................................................................................................34 
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SELECTION OF PATIENTS..........................................................................................................35 
7.1 
INCLUSION CRITERIA..................................................................................................................35 
7.2 
EXCLUSION CRITERIA ................................................................................................................36 
7.2.1 
Exclusion criteria related to study methodology ............................................................................36 
7.2.2 
Exclusion criteria related to study treatment..................................................................................37 
8 
STUDY TREATMENTS .................................................................................................................38 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTA.............................................................................38 
8.1.1 
Preparation and administration of cabazitaxel...............................................................................38 
8.1.1.1 
Preparation of the premix solution under aseptic conditions .........................................................39 
8.1.1.2 
Preparation of the infusion solution under aseptic conditions .......................................................39 
8.1.1.3 
Infusion conditions .........................................................................................................................39 
8.1.1.4 
Storage period of premix and infusion solution..............................................................................40 
8.1.1.5 
Recommendation for safe handling ...............................................................................................40 
8.1.2 
DOSAGE AND SCHEDULE ..........................................................................................................40 
8.1.2.1 
STUDY TREATMENTS..................................................................................................................41 
8.1.2.2 
Premedication ................................................................................................................................41 
8.1.2.3 
Dose modification and dose delay.................................................................................................41 
8.2 
OTHER INVESTIGATIONAL MEDICINAL PRODUCT(S).............................................................47 
8.2.1 
Administration ................................................................................................................................47 
8.2.2 
Guidelines for management of abiraterone-related adverse events..............................................47 
8.2.2.1 
Dose Reductions and Delay due to Toxicity related to Abiraterone Acetate.................................47 
8.2.3 
Management of Toxicity related to Abiraterone Acetate................................................................47 
8.2.3.1 
Management of Hypokalemia ........................................................................................................48 
8.2.3.2 
Management of Hypertension........................................................................................................48 
8.2.3.3 
Management of Fluid Retention/ Edema .......................................................................................49 
8.2.3.4 
Management of Abnormal Liver Function Tests............................................................................49 
8.2.3.5 
Management of Non-Mineralocorticoid Based Side Effects ..........................................................50 
8.2.3.6 
Drug interactions............................................................................................................................50 
8.2.4 
Guidelines for management of enzalutamide-related adverse events ..........................................50 
8.2.4.1 
Toxicity management.....................................................................................................................50 
8.2.4.2 
Drug interactions............................................................................................................................51 
8.3 
NON INVESTIGATIONAL MEDICINAL PRODUCT ......................................................................51 
8.4 
BLINDING PROCEDURES............................................................................................................52 
8.4.1 
Methods of blinding........................................................................................................................52 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................52 
8.5.1 
Patient number and treatment number ..........................................................................................52 
8.5.2 
Allocation of treatment(s)...............................................................................................................52 
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8.6 
PACKAGING AND LABELING ......................................................................................................52 
8.7 
STORAGE CONDITIONS AND SHELF LIFE................................................................................53 
8.8 
RESPONSIBILITIES ......................................................................................................................53 
8.8.1 
Treatment accountability and compliance......................................................................................53 
8.8.2 
Return and/or destruction of treatments ........................................................................................54 
8.9 
CONCOMITANT MEDICATION.....................................................................................................54 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................56 
9.1 
PRIMARY ENDPOINT ...................................................................................................................56 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................56 
9.2.1 
PSA endpoints ...............................................................................................................................56 
9.2.1.1 
PSA response ................................................................................................................................56 
9.2.1.2 
Time to PSA progression (TTPP) ..................................................................................................56 
9.2.2 
Progression free survival ...............................................................................................................57 
9.2.3 
Overall Survival..............................................................................................................................57 
9.2.4 
Tumor endpoints ............................................................................................................................57 
9.2.4.1 
Tumor response.............................................................................................................................57 
9.2.4.2 
Duration of tumor response ...........................................................................................................58 
9.2.5 
Pain endpoints ...............................................................................................................................58 
9.2.5.1 
Pain response ................................................................................................................................58 
9.2.5.2 
Time to pain progression ...............................................................................................................58 
9.2.6 
Symptomatic skeletal events .........................................................................................................59 
9.2.6.1 
SSE rate.........................................................................................................................................59 
9.2.6.2 
Time to occurrence of SSE ............................................................................................................59 
9.2.7 
Biomarkers.....................................................................................................................................59 
9.3 
SAFETY ENDPOINT......................................................................................................................59 
9.3.1 
Adverse events ..............................................................................................................................59 
9.3.2 
Laboratory safety variables............................................................................................................59 
9.3.3 
Vital signs.......................................................................................................................................60 
9.3.4 
Electrocardiogram variables ..........................................................................................................60 
9.4 
OTHER ENDPOINTS.....................................................................................................................60 
9.5 
FUTURE USE OF SAMPLES ........................................................................................................60 
10 
STUDY PROCEDURES ................................................................................................................61 
10.1 
VISIT SCHEDULE..........................................................................................................................61 
10.1.1 
Screening .......................................................................................................................................61 
10.1.2 
Randomization ...............................................................................................................................63 
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10.1.3 
During study treatment...................................................................................................................63 
10.1.4 
End of treatment.............................................................................................................................64 
10.1.5 
Follow-up period.............................................................................................................................65 
10.1.6 
Post study cut-off date ...................................................................................................................65 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................66 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................66 
10.3.1 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................67 
10.3.2 
List of criteria for permanent treatment discontinuation.................................................................67 
10.3.3 
Handling of patients after permanent treatment discontinuation ...................................................67 
10.3.4 
Procedure and consequence for patient withdrawal from study....................................................68 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................68 
10.4.1 
Definitions of adverse events.........................................................................................................68 
10.4.1.1 Adverse event ................................................................................................................................68 
10.4.1.2 Serious adverse event ...................................................................................................................68 
10.4.1.3 Adverse event of special interest...................................................................................................69 
10.4.2 
General guidelines for reporting adverse events ...........................................................................70 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................71 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................71 
10.5 
SAFETY INSTRUCTIONS .............................................................................................................72 
10.5.1 
Physical examination .....................................................................................................................72 
10.5.2 
Laboratory variables.......................................................................................................................72 
10.6 
ADVERSE EVENTS MONITORING..............................................................................................72 
11 
STATISTICAL CONSIDERATIONS..............................................................................................73 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................73 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................73 
11.3 
ANALYSIS POPULATIONS...........................................................................................................74 
11.3.1 
Efficacy populations .......................................................................................................................74 
11.3.1.1 Intent–to-treat population ...............................................................................................................74 
11.3.1.2 Evaluable populations....................................................................................................................74 
11.3.2 
Safety population ...........................................................................................................................74 
11.4 
STATISTICAL METHODS .............................................................................................................75 
11.4.1 
Extent of study treatment exposure ...............................................................................................75 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................75 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................75 
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11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................76 
11.4.2.3 Multiplicity considerations ..............................................................................................................76 
11.4.3 
Analyses of safety data..................................................................................................................76 
11.4.4 
Analyses of Pharmacogenetic variables........................................................................................77 
11.5 
INTERIM ANALYSIS......................................................................................................................77 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................78 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................78 
12.2 
INFORMED CONSENT .................................................................................................................78 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............78 
13 
STUDY MONITORING...................................................................................................................80 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................80 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................80 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................80 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................81 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................81 
14 
ADDITIONAL REQUIREMENTS...................................................................................................82 
14.1 
CURRICULUM VITAE....................................................................................................................82 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................82 
14.3 
CONFIDENTIALITY .......................................................................................................................82 
14.4 
PROPERTY RIGHTS.....................................................................................................................83 
14.5 
DATA PROTECTION.....................................................................................................................83 
14.6 
INSURANCE COMPENSATION....................................................................................................83 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................84 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................84 
14.8.1 
By the Sponsor...............................................................................................................................84 
14.8.2 
By the Investigator .........................................................................................................................85 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................85 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................85 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................86 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................87 
17 
APPENDICES................................................................................................................................91 
APPENDIX A. 
PSA ELIGIBILITY CHANGES AND PROGRESSION........................................................92 
APPENDIX B. 
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST1.1)...................................................................................................................................93 
APPENDIX C. 
ECOG PERFORMANCE STATUS SCALE......................................................................100 
APPENDIX D. 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS (9) ...............................................................................................................101 
APPENDIX E. 
BRIEF PAIN INVENTORY (SHORT FORM)....................................................................102 
APPENDIX F. WHO ANALGESIC LADDER FOR CANCER PAIN..........................................................104 
APPENDIX G. CYP 3A4 INHIBITORS AND CYP 3A4 INDUCERS (UPDATED NOVEMBER 2011).....105 
 
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LIST OF ABBREVIATIONS 
 
ACTH: 
Adrenocorticotropic hormone 
ADT: 
Androgen Deprivation Therapy 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
AR: 
androgen receptor 
AST: 
aspartate aminotransferase 
AUC: 
area under curve 
BUN: 
blood urea nitrogen 
CBZ: 
cabazitaxel 
cfDNA: 
circulating free Deoxyribonucleic Acid 
cfRNA: 
circulating free Ribonucleic acid 
CRF: 
Case Report Form 
CRPC: 
castration-resistant prostate cancer 
CTC: 
circulating tumor cells 
DLT: 
dose limiting toxicity 
DNA: 
Deoxyribonucleic acid 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EMA: 
European Medicines Agency 
EOT: 
end of treatment 
FDA: 
Food and Drug Administration 
GCP: 
Good clinical practice 
HLGT: 
high group level term 
HLT: 
high level term 
HR: 
hazard ratio 
ICH: 
International Conference on Harmonisation 
IMP: 
investigational medicinal product 
IRB/IEC: 
Institutional Review Board/Independent Ethics Committee 
ITT: 
intent to treat 
LDH: 
lactate deshydrogenase 
LH-RH: 
luteinizing hormone-releasing hormone 
mCRPC: 
metastatic Castration Resistant Prostate Cancer 
MTX: 
mitoxantrone 
NCI CTCAE: 
National Cancer Institute Common Terminology Criteria of Adverse Events 
OS: 
overall survival 
PCWG2: 
Prostate Cancer Working Group 2 
PD: 
progressive disease 
PSA: 
Prostate-Specific antigen 
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PT: 
preferred term 
RECIST: 
Response Evaluation Criteria In Solid Tumors 
rPFS: 
radiographic Progression-Free Survival 
SAE: 
Serious Adverse Event 
SGOT: 
Serum Glutamooxaloacétate Transférase 
SGPT: 
Serum Glutamo-Pyruvate Transferase 
SOC: 
System organ class 
SSE: 
symptomatic skeletal event 
TEAE: 
Treatment Emergent Adverse Events 
ULN: 
upper limit of normal 
WBC: 
white blood cell 
WHO: 
World Health Organization 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Prostate cancer is a major worldwide health problem and is the most frequently diagnosed male 
malignancy after lung cancer. Worldwide, there were 903,452 new cases and 258,381deaths due 
to prostate cancer alone during the year 2008 (13). Prostate cancer is associated with extensive 
morbidity, as most patients experience significant pain as the result of osseous metastases. 
Patients with advanced disease usually receive treatment with hormonal agents (orchiectomy, 
luteinizing hormone-releasing hormone [LH-RH] agonists and/or anti-androgens). However, the 
effect of ADT (Androgen Deprivation Therapy) is temporary, and most patients experience 
disease progression after 18 months of treatment. 
Although chemotherapy has historically been showed as modestly effective for the treatment of 
hormone resistant metastatic prostate cancer (HRMPC), recent studies have suggested that this 
may be changing. In 1990’s, randomized Phase III clinical trials comparing mitoxantrone plus 
corticosteroids to corticosteroids alone showed that mitoxantrone significantly increased the 
palliative effect of corticosteroid therapy (p = 0.01)(14)(15). Mitoxantrone became the first 
chemotherapy agent to be approved for the treatment of prostate cancer. However, there was no 
difference in survival between the treatment arms. 
Taxotere® in combination with prednisone was approved in 2004 for the treatment of androgen 
independent metastatic prostate cancer patients and demonstrated a 2.9 month survival benefit 
compared to mitoxantrone plus prednisone, prolonging survival from 16.5 months to 18.9 months 
(16). Standard of care in second line prostate evolved following the adoption of Taxotere® as 
standard first line therapy for Hormone Refractory Prostate Cancer (HRPC).  
A rapid evolution in the understanding of disease biology, combined with approvals of new 
therapies including immunotherapy, novel chemotherapy, hormonal agents and a bone calcium 
matrix-targeted radionuclide, along with further drugs in development, have made treatment 
decisions for metastatic castration-resistant prostate cancer (mCRPC) increasingly complex and 
challenging.  At the individual tumor level, the cellular states are dynamic (ie, one or all cell types 
may exist simultaneously within a tumor and their activity may evolve through adaptation or 
genomic events as the disease progresses).  Optimal treatment of CRPC, therefore, will involve 
identification of ligand-dependent versus -independent states, and individualization of therapies 
for different clinical states. Thus, distinguishing between patients with CRPC with preserved 
Androgen Receptor (AR) activity from those without AR activity has the potential to guide 
therapy for patients with advanced disease and may improve overall patient outcome. 
Furthermore, there is a paucity of evidence on how to better select the right patient for the right 
treatment and the manual for how to integrate these newly approved drugs for CRPC management 
needs to be investigated as a matter of urgency.   
Cabazitaxel is a next-generation taxane that has preclinical activity against docetaxel resistance 
tumor models, the ability to cross the blood–brain barrier and a tolerable safety profile consistent 
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with other approved chemotherapies. In the phase III TROPIC trial, cabazitaxel plus prednisone 
or prednisolone significantly improved overall survival (OS) in patients with mCRPC versus 
mitoxantrone plus prednisone or prednisolone, with a 30% reduction in the risk of death [hazard 
ratio (HR) 0.70; 95% confidence interval (CI) 0.59–0.83; P <0.0001; data cut-off 
25 September 2009] (10). Based on the results of the TROPIC trial, cabazitaxel (25 mg/m2 once 
every 3 weeks) plus prednisone was approved by the European Medicines Agency (EMA), Food 
and Drug Administration (FDA) and other national health authorities for the treatment of men 
with metastatic ‘hormone-refractory’ prostate cancer whose disease has progressed after receiving 
a docetaxel-containing regimen.  
The recognition of AR gene expression in CRPC in 2004 refocused research in the continued role 
of AR in CRPC.  This discovery changed the paradigm of treatment from the previous standard 
that all patients with disease progression on ADT were hormone-refractory.  It was recognized 
that even in castration-resistant disease, the AR remains a driver of tumor proliferation in some 
patients (17)(18)(19). 
Following this basic science breakthrough, several new AR targeted compounds entered into late 
phase clinical development for the treatment of advanced prostate cancer. Abiraterone acetate and 
Enzalutamide have successfully demonstrated efficacy and safety in both chemo-naïve and post 
chemotherapy mCRPC patients (6)(7)(8)(9).  These data led to the FDA and EMA approval of 
using abiraterone acetate for both chemo-naïve and post chemotherapy mCRPC patients and 
enzalutamide for mCRPC patient post docetaxel treatment. It is also expected that the recent 
positive interim analysis from the PREVAIL study (9) which showed overall survival benefit of 
enzalutamide comparing to placebo will likely support the approval of enzalutamide for the 
chemo-naïve mCRPC patients in 2014. Thus, the mCRPC treatment landscape for chemo-naïve 
mCRPC patients is going through a significant change for the coming years.  
4.2 
INVESTIGATIONAL MEDICINAL PRODUCT 
4.2.1 Preclinical data 
Cabazitaxel (also known as XRP6258, RPR116258A) is a semisynthetic compound derived from 
the 10-deacetyl Baccatin III, which is extracted from European yew needles. This new taxoid 
which promotes the tubulin assembly in vitro and stabilizes microtubules against cold-induced 
depolymerization as efficiently as docetaxel was selected for development based on a better 
antiproliferative activity on resistant cell lines than docetaxel. Using cell lines with acquired 
resistance to doxorubicin, vincristine, vinblastine, paclitaxel and docetaxel, the resistance factors 
ranged from 1.8 to 10 and 4.8 to 59, for cabazitaxel and for docetaxel, respectively.  Cabazitaxel 
exhibited a broad spectrum of in vivo antitumor activity, not only in docetaxel -sensitive tumor 
models, but also in tumors models in which docetaxel was either poorly active or not active. A 
trend for schedule-dependency was observed with maximum tolerated dosages 4.8-fold higher 
with an intermittent schedule than with a split dose schedule. The best antitumor efficacy was 
obtained with the schedules allowing the administration of the highest amount of drug. In 
addition, this compound was found to penetrate the blood brain barrier and marked antitumor 
activity was obtained in nude mice bearing intracranial glioblastomas.  
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More information on the preclinical data is available in the clinical Investigator’s brochure (20). 
4.2.2 Summary of clinical data 
In single agent, 3 Phase I studies were conducted to determine the schedule and the recommended 
dose, one study investigating the disposition of radiolabeled cabazitaxel, one Phase 2 study in 
patients with metastatic breast cancer (MBC), and one Phase 3 study in patients with mCRPC. 
One Phase I/II study has been conducted with cabazitaxel plus prednisone in combination with 
capecitabine. 
4.2.2.1 Phase 1 
The 3 Phase 1 studies in solid tumors (TED6188, TED6189, TED6190) have been completed.  
There were 2 partial responses in patients with prostate cancer in Phase 1 studies evaluating the 
every 3 week schedule; 2 PR out of 8 patients with metastatic HRPC in TED6190 at 25 mg/m2 
suggesting potential biological and clinical activity in patients with prostate cancer.   
The safety profile was comparable in TED6188 and TED6190, with the intermittent schedule 
(1-hour infusion every 3 weeks).  The dose limiting toxicity (DLT) of cabazitaxel was neutropenia 
and its infectious complications at the highest dose tested, 30 mg/m² in TED6188 and 25 mg/m² in 
TED6190. 
As a result, the dose levels of 20 mg/m² and 25 mg/m² every 3 weeks were defined as the 
recommended doses for further clinical development with the intermittent schedule. 
In TED6189 with the weekly schedule, the maximum tolerated dose (MTD) was reached at 
12 mg/m², at which the DLT was diarrhea.  As a result, the dose level of 10 mg/m² was defined as 
the recommended dose for further clinical development with this weekly schedule.   
In TCD6945 the recommended dose was defined as cabazitaxel 20 mg/m² on D1 and capecitabine 
1000 mg/m² twice daily from D1 to D14, every 3 weeks. DLT were all grade 4 neutropenia lasting 
more than 7 days.   
4.2.2.2 Phase 2 
One Phase 2 study in patients with taxane- and/or anthracycline-resistant metastatic breast cancer 
has been completed (ARD6191). In this study patients were treated with a starting dose of 
20 mg/m2 cabazitaxel every 3 weeks with the option to dose-escalate cabazitaxel based on 
favorable tolerability at Cycle 1. In 20 of 71 patients, the cabazitaxel dose was escalated from 20 
to 25 mg/m2 after the first cycle. The most frequently occurring toxicities overall were Grade 3 
and 4 neutropenia (73.2%), fatigue (50.7%), nausea (43.7%), diarrhea (39.4%), myalgia (25.4%), 
anorexia (25.4%), weight loss (25.4%), and vomiting (23.9%). The overall response rate was 
14.1% with 2 complete responses (CR) and 8 partial responses (PR). 
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4.2.2.3 Phase 3 
One Phase 3 study was conducted in mCRPC patients previously treated with docetaxel 
containing regimen. This study compared cabazitaxel (CBZ) plus prednisone to mitoxantrone 
(MTX) plus prednisone (EFC6193). A total of 755 patients were randomized (378 patients in 
CBZ arm and 377 patients in MTX arm). A statistically significant increase in OS was observed 
in patients treated with CBZ plus prednisone compared to patients treated with MTX plus 
prednisone, with a HR of 0.70 (95%CI: 0.59 – 0.83), a log-rank p-value of 0.0001. The median 
OS was 15.1 months (95%CI: 14.1 – 16.3) in CBZ arm versus 12.7 months (95%CI: 11.6–13.7) in 
MTX arm.  
The secondary endpoints also demonstrated a net benefit in favor of CBZ treated patients 
compared with MTX treated patients. Progression-free survival, defined as the earliest date of 
radiological tumor progression, PSA progression, pain progression, or symptom deterioration or 
death due to any cause, was statistically significantly longer in the CBZ group compared with the 
MTX group (p<0.0001, HR = 0.74 [95% CI, 0.64-0.86]), and median progression-free survival 
was 2.8 months versus 1.4 months. Response rates for PSA and tumor assessments, as well as the 
time to PSA and tumor progression when defined as radiological progression or death were 
statistically significant in favor of CBZ. Pain response and time to pain progression were not 
statistically different between CBZ and MTX, for which the primary basis for approval was pain 
relief and control. 
Treatment emergent AEs were experienced by 95.7% of patients in the CBZ group and 88.4% of 
patients in the MTX group; 57.4% of patients in the CBZ group and 39.4% of patients in the MTX 
group had at least one Grade 3-4 TEAE. In the CBZ group 39.1% of patients had at least 1 
Serious Adverse Event (SAE) compared with 20.8% of patients in the MTX group. Study 
treatment discontinuation due to a TEAE was reported in 18.3% of patients in the CBZ group and 
8.4% of patients in the MTX group. 
The most frequent toxicity in the CBZ group were neutropenia and its clinical consequences of 
febrile neutropenia and infections. Based on laboratory assessments, 81.7% of patients in the CBZ 
group and 58.0% of patients in the MTX group had grade 3-4 neutropenia.  Patients treated with 
CBZ also had higher rates of infections Grade 3-4 with or without concomitant severe neutropenia 
(10.2% CBZ, 5.1% MTX) and febrile neutropenia (7.5% CBZ, 1.3% MTX). 
Gastrointestinal disorders of all types (Grade 3-4) were more common in the CBZ group (12.4% 
CBZ, 1.6% MTX). Notably, Grade 3-4 diarrhea was more common on CBZ (6.2%) compared 
with MTX (0.3%). Incidence of Grade 3-4 stomatitis (0% in both groups) and mucositis (0.3% in 
both groups) was similar in both treatment groups. 
Adverse events in the renal and urinary disorders System Organ Class (SOC) (Grade 3-4) also 
were more common in the CBZ group (8.6% CBZ, 2.4% MTX). These events consisted of renal 
failure and impairment (3.2% CBZ, 0.3% MTX) as well as renal obstructive disorders (0.8% 
CBZ, 0.5% MTX). In the CBZ group, 15 patients were reported to have acute renal Adverse 
Events (AEs) Grade 3-4, the etiology of which was multifactorial consisting of pre-renal, renal, or 
obstructive causes. According to laboratory values, the incidence of all grade /grade 3-4 creatinine 
increase was 15.6%/1.3% in CBZ arm and 11.6%/0.5% in MTX. In addition, more hematuria was 
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reported in CBZ arm versus MTX arm (62 patients/16.7% versus 14 patients/3.8%). In CBZ arm, 
no clear possible explanation such as local infection/obstruction/progression, or 
anticoagulation/aspirin therapy, or thrombocytopenia was found for 21 patients. In prior studies 
conducted in metastatic breast cancer, a total of 6 patients (2 in the ARD6191 and 4 in the 
TCD6945) experienced cystitis without local infection including 5 hemorrhagic cystitis (3 cystitis 
were documented with biopsy). Of note, in human the urinary excretion of cabazitaxel is about 
3.7% of the dose with 2.3% excreted as unchanged drug. 
Death within 30 days due to AE occurred in 18 patients (4.9%) in the CBZ group and 3 patients 
(<1.0%) in the MTX group. Of the 18 deaths in the CBZ group, 7 were the result of neutropenia 
and/or infection, 5 were due to cardiac events (2 cardiac arrest, 1 cardiac failure, 1 dyspnea and 
1 ventricular fibrillation), 1 was due to dehydration and hydro-electrolyte imbalance, 3 were pre- 
or post-renal events leading to renal failure, and 2 were due to other causes, including a death of 
unknown etiology and a death from a cerebral hemorrhage following a fall in a patient taking 
concomitant clopidrogrel.  
Based on the results of this study, a dossier to register cabazitaxel in hormone refractory 
metastatic prostate cancer patients previously treated with Taxotere® containing regimen has been 
submitted in several countries worldwide Cabazitaxel in combination with prednisone or 
prednisolone is currently approved in the United States, the European Union, Canada, 
Switzerland, and numerous other countries in Latin America, Asia, and the Middle East. 
4.3 
STUDY RATIONALE 
While abiraterone acetate in association with prednisone or enzalutamide provided significant 
improvements in the mCRPC patients, not all patients treated with the AR-targeted agents 
responded to the treatments.  Early radiological progression within the first 3 months, was noted 
in about 1 of every 4 patients treated with enzalutamide in the AFFIRM study (Phase III study of 
enzalutamide in post-chemo setting) (8). Similarly, in the COU-AA-301 phase 3 study of 
abiraterone acetate conducted in mCRPC patients with prior exposure to docetaxel, early 
progression was noted in about 1 of every 3 patients (6). Moreover, almost 50% of patients 
experienced disease progression at month 6. Recently, two large randomized Phase 3 trials have 
demonstrated the clinical benefit of treating chemo-naive mCRPC patients with abiraterone 
(COU-AA-302) (7) or enzalutamide (PREVAIL) (9). Despite of earlier treatment with potent 
novel AR targeted therapies, around 20-25% of the patients experienced early progression of the 
disease within first 6 month which clearly suggested the ligand independent nature of a subset of 
the CRPC and confirmed the heterogeneity of the CRPC. 
Interestingly, in a separate study of abiraterone acetate in association with prednisone in 
57 patients with CRPC and bone metastases, a subgroup of patients 14 patients (25%) experienced 
no clinical benefit. These patients, who had no symptomatic improvement and no objective 
evidence of tumor regression, were considered to exhibit primary resistance to abiraterone acetate.  
The further examination of the bone marrow biopsies of these patients revealed that a lack of 
nuclear AR and cytoplasmic CYP17 in bone marrow were associated with primary resistance. 
Thus, these data support the tumor biological differences between different mCRPC patients and 
warrant further exploration of alternative treatment options (21).  
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More recently, Emmanuel Antonarakis from Johns Hopkins Universty, published data about 
AR-V7 and resistance to abiraterone acetate and enzalutamide (22). Detection of AR-V7 in CTCs 
from patients with CRPC may be associated with resistance to enzalutamide and abiraterone. 
A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of 
whom 39% and 19%, respectively, had detectable AR-V7 in CTCs. Among men receiving 
enzalutamide, AR-V7 positive patients had lower PSA response rates than AR-V7 negative 
patients (0% vs. 53%, P = 0.004) and shorter PSA progression-free survival (median, 1.4 months 
vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months 
vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P = 0.002). 
Similarly, among men receiving abiraterone, AR-V7 positive patients had lower PSA response 
rates than AR-V7 negative patients (0% vs. 68%, P = 0.004) and shorter PSA progression-free 
survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free 
survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6months 
vs. not reached, P = 0.006). 
The biological heterogeneity of the CRPC and the adaptation of the tumor cells to the 
microenvironment clearly indicate the needs for an effective AR independent tumor targeting 
strategy and the importance of distinguish these patients with primary resistance to AR targeted 
therapy with appropriate monitoring during the treatment.   
COU-AA-302 study is the pivotal study of studying abiraterone acetate’s activity in the 
chemo-naïve mCRPC patient population and subsequently led to the approval by the FDA for 
using abiraterone for the treatment of mCRPC patients prior to docetaxel treatment. Additional 
analyses were also performed including the  response. Although treatment decisions for 
COU-AA-302 were not made on the basis of PSA alterations, other studies have suggested a 
prognostic value of PSA declines of 50% or greater from baseline in relation to survival with a 
variety of therapies in patients with mCRPC. In an exploratory analysis of COU-AA-302, Ryan et 
al. examined the relationship between baseline PSA and degree of PSA decline with radiographic 
Progression-Free Survival (rPFS) and other clinical efficacy outcomes in patients with mCRPC 
treated with abiraterone acetate (23). This analysis found that PSA decline rates were greater and 
the degree of decline higher in the abiraterone acetate treatment arm compared with the 
prednisone arm. Interesting, they also found that rPFS, OS, and TTPP were positively associated 
with the magnitude of PSA decline and inversely associated with baseline PSA in a step-wise 
fashion. Importantly, the patient group who has not achieved a PSA response as defined by 50% 
decline from the baseline in response to treatment was associated with no or limited 
improvements in clinical outcomes compared to patients who had a PSA response. Thus it is 
important to investigate the PSA kinetics in patients treated with AR targeted therapy to quickly 
identify the patients who might have limited benefit from AR targeted therapy. In addition, 
Rathkopf published data suggesting that the median TTPP is 11.1 months for patients treated with 
abiraterone Acetate in chemo-naïve patients (24). 
Hormonal intra-class cross resistance has been reported recently. While the mechanisms of action 
of enzalutamide and abiraterone acetate differ by either direct inhibition of AR or inhibition of 
extragonadal androgen synthesis, both target AR signaling. Two retrospective studies evaluating 
the antitumor activity of abiraterone acetate in patients with CRPC who progressed following 
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treatment with enzalutamide have documented lower PSA response rates and smaller decreases in 
PSA.  
In these studies, a small population of patients sequentially treated with abiraterone acetate after 
having received docetaxel and enzalutamide, both studies reported that only a small subset of 
patients showed significant benefit from sequential treatment. In the first study (25), among 
38 patients, abiraterone acetate resulted in 50% decrease in PSA in only 3 patients (1 who failed 
to respond to enzalutamide and 2 with prior response to enzalutamide) suggesting clinical cross 
resistance between the AR-targeted agents. These findings mirror the second study of a 
multicenter review of 30 patients treated with enzalutamide followed by abiraterone acetate 
treatment. In the second study, abiraterone acetate, administered for a median of 13 weeks, 
resulted in no objective radiographic responses.  Best response to enzalutamide was 90%, 50% 
and 30% decrease in PSA in 23%, 63% and 70% of patients, respectively. In contrast, the best 
response to abiraterone acetate was 90%, 50% and 30% decrease in PSA in 0%, 3% and 11% of 
patients, respectively.  Among the 21 patients with prior 30% decrease in PSA on enzalutamide, 
only one patient had a >30% decline in PSA with abiraterone acetate (26).   
Similar to the observation of switching from enzalutamide to abiraterone acetate, the reduced 
response rate was also observed when patients received enzalutamide treatment post abiraterone 
acetate therapy from several retrospective studies. A pilot study evaluated the biochemical 
response to enzalutamide in 35 patients with CRPC who had previously received docetaxel 
followed by abiraterone acetate.  A decrease in PSA >50% was achieved by 10 (28.6%) patients.  
Patients with >50% response in PSA had a significantly longer mean duration of enzalutamide 
than those who did not (7.8 months versus 3.8 months; P=0.001).  The patients with failure to 
respond to enzalutamide had higher Gleason scores (8-10).  A significant decline in PSA (>50%) 
was observed in 7 of 16 patients who had shown a similar response to abiraterone acetate in and in 
3 of 19 patients (15.8%) who had no significant response to abiraterone acetate.  Clinical response 
or stabilization of condition was observed in 19 (54.3%) of patients including six patients who had 
no biochemical response (27).   
In a second retrospective study of enzalutamide, conducted in post-docetaxel patients also treated 
with prior abiraterone acetate, 39 patients were treated and 22 (56%) had no PSA decline as their 
best response. A total of 9 patients (23%) had a PSA decline of >50% but only 5 of these patients 
had a confirmed >50% PSA decline. Thus many of the reported declines in PSA were short-lived. 
Of the 15 patients with a >50% PSA response after abiraterone acetate, 2 had >50% PSA response 
to enzalutamide. Of the 22 patients without a response to abiraterone acetate, 2 had a >50% PSA 
response to enzalutamide. The median duration of treatment was only 2.9 months and median 
time to progression was 2.8 months. This compares to a median time to progression of 8.3 months 
in the phase III post-docetaxel AFFIRM trial. In the AFFIRM trial the RECIST response rate was 
29% as compared to a RECIST response rate of 4% in this retrospective analysis (28).  
More recently, the post hoc analysis of the COU-AA-302 study revealed that 88 patients who 
have received a second AR targeted treatment post abiraterone experienced modest clinical 
response rates and short treatment duration (2.8 to 3.8 month) (12). 
Thus, although the data are minimal and mainly from retrospective reports, there is a strong 
suggestion of cross-resistance between abiraterone acetate and enzalutamide although one could 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To demonstrate the superiority in term of radiographic Progression-Free Survival (rPFS) [using 
Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and PCWG2 (1)(2) of cabazitaxel at 
25 mg/m² plus prednisone (Arm A) versus either enzalutamide at 160 mg once daily or 
abiraterone acetate at 1000 mg once daily plus prednisone (Arm B) in chemotherapy-naïve 
patients with mCRPC who have disease progression while receiving AR targeted therapy 
(abiraterone plus prednisone or enzalutamide) within 12 months of treatment initiation 
(12 months). 
5.2 
SECONDARY 
x 
To compare efficacy of  cabazitaxel plus prednisone to enzalutamide or abiraterone acetate 
plus prednisone for: 
- 
PSA response rate, 
- 
Progression Free Survival (PFS),  
- 
Overall Survival (OS), 
- 
Time To PSA Progression (TTPP),  
- 
Tumor response rate in patients with measurable disease (RECIST 1.1), 
- 
Duration of tumor response, 
- 
Pain response, 
- 
Time To Pain Progression,  
- 
Symptomatic skeletal events (SSE) rate, 
- 
Time to occurrence of any SSE, 
x 
To analyze messenger RNAs including androgen-receptor splice variant 7 messenger RNA 
(AR-V7) at baseline and post-treatment in Circulating Tumor Cells (CTCs).  
x 
To evaluate safety in the 2 treatment arms 
5.3 
  
x 
To analyze Circulating Tumor Cells (CTCs) phenotypes as well as expression and 
localization of proteins including androgen receptors (AR) isoforms in CTCs at baseline. 
x 
To collect circulating free nucleic acids (cfDNA and cfRNA) derived from plasma at 
baseline, on treatment and post-treatment for biomarker studies.  
x 
To collect germline DNA derived from whole blood at baseline for biomarker studies and 
subtractive mutation analysis. 
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6 
STUDY DESIGN 
This is a prospective, multicenter, multinational, randomized, open label study, comparing the 
efficacy of cabazitaxel at 25 mg/m² plus prednisone (Arm A) versus either enzalutamide at 
160 mg once daily or abiraterone acetate at 1000 mg once daily plus prednisone (Arm B). 
Resistant population is defined as patients who have disease progression while receiving 
AR targeted therapy within 12 months of treatment (12 months) (3). 
6.1 
DESCRIPTION OF THE PROTOCOL 
Treatment allocation will be performed by an Interactive Voice/Web Response System 
(IVRS/IWRS). All eligible patients will be randomly assigned to either arm A or B in a 1:1 
proportion. 
Randomization will be stratified by:  extra nodal visceral metastases (yes, no), and level of PSA 
decline within 12 months of initiation of AR targeted therapy (no decline, decline 1% to <50%, 
decline 50%) and time from AR targeted agent initiation to progression 
([0; 6 months], ]6; 12 months]). 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
Each patient will be treated until radiographic disease progression, unacceptable toxicity, or 
patient’s refusal of further study treatment. The study period will include the screening phase, the 
study treatment period (until 30 days after last cabazitaxel or abiraterone acetate or enzalutamide 
administration) and the follow-up period. Cabazitaxel will be administered every 3 weeks. The 
comparators will be given orally continuously. The first study treatment should be administered 
within 7 calendar days after randomization. The time between biological work-up and first cycle 
should not exceed 8 days. If it is the case, hematology and biochemistry should be done again 
before first cycle in order to check that eligibility criteria are still met. After study treatment 
discontinuation, patient will be followed every 12 weeks until death, cut-off date or withdrawal of 
patient’s consent, whichever comes first. During the follow-up period, ongoing related AEs at end 
of treatment and all (serious or non-serious) new adverse events related to study treatment will be 
collected and followed until resolution or stabilization. 
Patients still on study treatment at the cut-off date can continue treatment until at least 1 treatment 
permanent discontinuation criterion as defined in Section 10.3.2 is met.  
If a patient discontinues study treatment due to reason other than radiographic progressive disease, 
investigator may consider not initiating further anticancer therapy before radiographic progression 
is documented. In case it occurs within the 4 first cycles, initiation or not of further anticancer 
therapy before radiographic progression is documented, is left to the investigator decision. 
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6.2.2 Determination of end of clinical trial (all patients) 
The study is event driven and the final cut-off date will be when 155 disease progression events 
have occurred (expected to occur around 30 months from first patient in). 
End of trial will occur 30 days after the last patient last cycle. 
6.3 
INTERIM ANALYSIS 
No Interim analysis is planned. 
6.4 
STUDY COMMITTEES 
A Steering Committee (SC), including the 3 Study Chairmen and sponsor representatives, will be 
responsible for:  
x 
Supervising the progress of the trial towards its overall objectives, 
x 
Reviewing at regular intervals relevant information that may affect the study conduct,  
 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
Patients meeting all the following criteria will be considered eligible for enrolment into the study: 
I 01. Diagnosis of histologically or cytologically confirmed prostate adenocarcinoma  
I 02. Metastatic disease 
I 03. Progressive disease (PD) while receiving AR targeted therapy with abiraterone acetate or 
enzalutamide within 12 months of treatment initiation (12 months) by at least one of the 
following: 
a) Progression in measurable disease (RECIST 1.1 criteria). Patient with measurable 
disease must have at least one lesion that can be accurately measured in at least one 
dimension (longest diameter to be recorded). Each lesion must be at least 10 mm when 
measured by computed tomography (CT) [CT scan thickness no greater than 5 mm] or 
magnetic resonance imaging (MRI). Lymph nodes should be 15 mm in short axis. As 
defined by PCWG2, if lymph node metastasis is the only evidence of metastasis, it 
must be 20 mm in diameter when measured by spiral CT or MRI. Previously 
irradiated lesions, primary prostate lesion and bone lesions will be considered non-
measurable disease, and/or 
b) Appearance of 2 or more new bone lesions. They must be confirmed by other imaging 
modalities (CT; MRI) if ambiguous results (PCWG2), and/or 
c) Rising PSA defined (PCWG2) as at least two consecutive rises in PSA to be 
documented over a reference value (measure 1) taken at least one week apart. The first 
rising PSA (measure 2) should be taken at least 7 days after the reference value. A 
third confirmatory PSA measure is required (2nd beyond the reference level) to be 
greater than the second measure and it must be obtained at least 7 days after the 2nd 
measure. If this is not the case, a fourth PSA measure is required to be taken and be 
greater than the 2nd measure. The third (or the fourth) confirmatory PSA should be 
taken within 4 weeks prior to randomization Appendix A. In case of progression based 
on rising PSA only, the first rising PSA (measure 2) must be obtained within 6 months 
of initiation of AR targeted therapy (6 months). 
Duration of the first AR targeted agent treatment should not exceed 12 months for patients 
with PD within 6 months and should not exceed 18 months for those with PD between 6 
and 12 months. 
I 04. A PSA value of at least 2 ng/mL is required at study entry. 
I 05. Effective castration (serum testosterone levels <0.5 ng/mL).  
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I 06. Prior AR targeted therapy (abiraterone acetate or enzalutamide) must be stopped at least 
2 weeks before study treatment. 
I 07. Signed written informed consent. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 2 subsections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. Prior chemotherapy for prostate cancer, except estramustine and except 
adjuvant/neoadjuvant treatment completed >3 years ago. No further anti-cancer therapy 
after the previous AR targeted therapy and before inclusion. Prior docetaxel in hormone 
sensitive setting is allowed if completed >1 year before randomization (4). Prior 
immunotherapy is allowed. 
E 02. Less than 28 days elapsed from prior treatment with immunotherapy, radiotherapy or 
surgery to the time of randomization.   
E 03. Adverse events (excluding alopecia and those listed in the specific exclusion criteria) from 
any prior anticancer therapy of grade >1 (National Cancer Institute Common Terminology 
Criteria of Adverse Events [NCI CTCAE] v4.0) at the time of randomization. 
E 04. Less than 18 years (or country’s legal age of majority if the legal age is >18 years). 
E 05. Eastern Cooperative Oncology Group (ECOG) performance status >1. 
E 06. History of brain metastases, uncontrolled spinal cord compression, or carcinomatous 
meningitis or new evidence of brain or leptomeningeal disease. 
E 07. Prior malignancy. Adequately treated basal cell or squamous cell skin or superficial (pTis, 
pTa, and pT1) bladder cancer are allowed, as well as any other cancer for which treatment 
has been completed  5 years ago and from which the patient has been disease-free for 
5 years.  
E 08. Participation in another clinical trial and any concurrent treatment with any investigational 
drug within 30 days prior to randomization. 
E 09. Acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV disease 
requiring antiretroviral treatment. 
E 10. Any severe acute or chronic medical condition including uncontrolled diabetes mellitus, 
severe renal impairment, history of cardiovascular disease (uncontrolled hypertension, 
arterial thrombotic events in the past 6 months , congestive heart failure, severe or unstable 
angina pectoris, recent myocardial infraction within last 6 months or uncontrolled cardiac 
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arrhythmia), which could impair the ability of the patient to participate to the study or 
interfere with interpretation of study results, or patient unable to comply with the study 
procedures. 
E 11. Patients with reproductive potential who do not agree to use accepted and effective method 
of contraception during the study treatment period and up to 6 months after the last 
administered dose. The definition of “effective method of contraception” will be based on 
the investigator’s judgment. 
7.2.2 Exclusion criteria related to study treatment  
E 12. Known allergies, hypersensitivity or intolerance to prednisone or excipients of abiraterone 
acetate or enzalutamide. History of hypersensitivity to docetaxel or polysorbate 80. 
E 13. Known history of mineralocorticoid excess or deficiency (not applicable to patients who 
have already been treated with abiraterone acetate in first line before inclusion). 
E 14. History of seizure, underlying brain injury with loss of consciousness, transient ischemic 
attack within the past 12 months, cerebral vascular accident, brain arteriovenous 
malformation or the use of concomitant medications that may lower the seizure threshold 
(not applicable to patients who have already been treated with enzalutamide in first line 
before inclusion). 
E 15. Unable to swallow a whole tablet or capsule. 
E 16. Inadequate organ and bone marrow function as evidenced by: 
a) Hemoglobin <10.0 g/dL 
b) Absolute neutrophil count <1.5 x 109/L 
c) Platelet count <100 x 109/L  
d) AST/SGOT and/or ALT/SGPT >1.5 x ULN; 
e) Total bilirubin >1.0 x ULN 
f) 
Potassium <3.5 mmol/L 
g) Serum albumin <3.0 g/dL 
h) Child-Pugh Class B and C 
E 17. Contraindications to the use of corticosteroid treatment. 
E 18. Symptomatic peripheral neuropathy grade 2 (National Cancer Institute Common 
Terminology Criteria of Adverse Events [NCI CTCAE] v4.0). 
E 19. Concomitant vaccination with yellow fever vaccine. 
 
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8 
STUDY TREATMENTS 
Name and formulation details of drugs used in study are summarized in Table 1 below. 
Table 1 - Study treatments 
Drug code 
XRP6258 
- 
INN  
cabazitaxel 
prednisone or 
prednisolone 
Formulation 
Cabazitaxel is supplied as a sterile, non-pyrogenic, non-aqueous 
yellowish to brownish yellow solution contained in a 15 mL clear glass 
vial, stoppered with a chlorobutyl rubber closure coated with a 
transparent ETFE coating. The rubber closure is crimped to the vial 
with an aluminum cap covered with a light green plastic flip-off cap. 
Single-dose vial, containing a total of 60 mg of cabazitaxel expressed 
as anhydrous and solvent-free basis, per 1.5 mL of solution. The fill 
volume has been established to include an overfill [ie, 1.5 mL (nominal 
volume) + 0.33 mL]. This overfill was determined to ensure that a 
10 mg/mL concentration is obtained in the premix and that 60 mg dose 
can be extracted. 
The solvent used for the preparation of the premix is a sterile, non-
pyrogenic solution containing a 13% w/w ethanol solution in water for 
injection. This solution is contained in a 15 mL clear glass vial, 
stoppered with a chlorobutyl rubber closure coated with a transparent 
ETFE coating. The rubber closure is crimped to the vial with either an 
aluminum cap covered with a light grey plastic flip-off cap or a gold-
color aluminum cap covered with a clear plastic flip-off cap. 
Each vial of solvent is overfilled to ensure that a 10 mg/mL 
concentration is obtained in the Premix and that 60 mg dose can be 
extracted. [ie, 4.5 mL (nominal volume) + 1.17 mL]. The solution is a 
clear colorless liquid. 
Commercially available 
formulation 
(refer to the local labeling) 
Storage conditions 
Store at 25°C (77°F); excursions permitted between 15°-30°C 
(59°- 86°F). Do not refrigerate. The solvent was also shown to be 
stable under these conditions. All vials must be kept in their box until 
use. 
Refer to the local labeling. 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTA 
CABAZITAXEL 
8.1.1 Preparation and administration of cabazitaxel 
The preparation of the cabazitaxel (XRP6258) infusion solution for administration requires the 
preparation of a premix solution at 60 mg/6 mL (nominal concentration).  This must be done with 
a 13% w/w ethanol solution in water for injection (the “solvent”) supplied with the cabazitaxel 
concentrate for solution for infusion (“preparation of the premix solution”).  Then the premix 
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solution must be diluted in an infusion vehicle (“preparation of the infusion solution”) prior to 
administration.  
8.1.1.1 Preparation of the premix solution under aseptic conditions 
Set aside the required number of solvent vials (one solvent vial for each vial of cabazitaxel).  For 
each cabazitaxel vial: 
x 
Using a syringe fitted with a needle, withdraw the ENTIRE CONTENTS of the solvent 
vial and inject it into the corresponding vial of cabazitaxel. 
x 
The addition of the ENTIRE CONTENTS of 1 solvent vial ensures a minimal extractable 
volume of the premix solution of 6 mL, containing 10 mg/mL of cabazitaxel. 
x 
Remove the syringe and needle and gently mix the reconstituted solution by repeated 
inversions for at least 45 seconds. Do not shake. 
x 
Allow the premix solution to stand for 5 minutes at room temperature to allow foam to 
dissipate. The solution is homogeneous and contains no visible particulate matter. It is 
normal for foam to persist after this time period. 
The premix solution contains 10 mg/mL of cabazitaxel. Then the premix solution must be diluted 
in an infusion vehicle so as to obtain the required dose for administration. 
8.1.1.2 Preparation of the infusion solution under aseptic conditions 
WARNING: Since foam is normally present, the required dose must be accurately adjusted using 
a graduated syringe. 
x 
Aseptically, with a syringe and needle, withdraw the volume of the premix solution 
containing 10 mg/mL of cabazitaxel that corresponds to the required dose (mg) for 
administration of cabazitaxel 
x 
Inject the required premix volume into a 125 or 250 or 500 mL infusion container 
(containing either 5% glucose solution or 0.9% sodium chloride solution). 
The concentration of the infusion should be between 0.10 mg/mL and 0.26 mg/mL (based on 
Maximum Tolerated Dose of 30 mg/m² and a Body Surface Area [BSA] of 2.1 m²).  
Mix the contents of the infusion container manually by gently inverting the bag or bottle. 
8.1.1.3 Infusion conditions 
The recommended infusion duration is 1 hour. The infusion solution should be used within 
8 hours at ambient temperature (including the one hour infusion time) or within a total of 48 hours 
if refrigerated (including the 1 hour infusion time). 
The infusion solution should be administered at room temperature under normal lighting 
conditions. 
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Do not use PVC infusion containers or polyurethane infusion sets for cabazitaxel preparation and 
administration. 
Glass bottles could also be used. 
Use and in-line filter of 0.22 μm nominal pore size (also referred to as 0.2 μm) during cabazitaxel 
administration. 
8.1.1.4 Storage period of premix and infusion solution 
The premix solution of cabazitaxel should be used immediately after preparation and within 
1 hour at ambient temperature. 
The infusion solution is stable for 8 hours at ambient conditions (including the 1 hour infusion 
time) or a total of 48 hours if refrigerated, from preparation to end of infusion. 
8.1.1.5 Recommendation for safe handling 
Cabazitaxel is an anti-neoplastic agent and, like other potentially toxic compounds, caution should 
be exercised in handling and preparing cabazitaxel solutions. The use of gloves is recommended. 
If cabazitaxel concentrate, premix solution, or infusion solution should come into contact with 
skin, wash immediately and thoroughly with soap and water. If cabazitaxel concentrate, premix 
solution, or infusion solution should come into contact with mucous membranes, wash 
immediately and thoroughly with water. 
8.1.2 DOSAGE AND SCHEDULE 
BSA will be calculated prior to each treatment cycle from body weight in kg, recorded prior to 
each treatment cycle, and height in cm, recorded at baseline. The preferred Dubois and Dubois 
equation is: BSA in units of m2 = wgt in kg 0.425 x hgt. in cm 0.725 x 0.007184. 
The treatment should continue for at least 12 weeks (4 cycles) in the absence of radiological 
evidence of disease progression defined in Section 9.1 or unacceptable toxicity or patient refusal 
of further treatment. Subsequently, no decision of treatment discontinuation should be made in 
case of PSA increase ALONE or pain increase ALONE, within the first 12 weeks see Sections 
9.2.1.2 and 9.2.5.2. 
Each patient will be treated until radiographic progressive disease, unacceptable toxicity, patient’s 
refusal of further study treatment or any other discontinuation criteria as defined in Section 10.3.2. 
In case of patient discontinues study treatment due to reason other than radiological progressive 
disease, the investigator may consider not to initiate further anticancer therapy before radiological 
progression is documented (as defined in Section 9.1), in case study treatment discontinuation  
occurs within the 4 first cycles the decision is left to investigator judgment. 
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8.2.3.1 Management of Hypokalemia 
At the initial observation of Grade 1 or 2 hypokalemia (serum potassium <3.5 mM or below lower 
limit of normal range, but t3.0 mM), oral potassium supplement will be initiated. The dose of 
potassium supplement must be carefully titrated to maintain serum potassium from 3.5 to 5.0 mM, 
inclusive. Any subject with low potassium during the study or a history of hypokalemia from a 
preexisting or concurrent medical condition will undergo at least weekly laboratory electrolyte 
evaluation until recovery to the range 3.0 mM. The investigator should consider maintaining 
potassium t4.0 mM in these subjects Table 6. 
If any subject experiences Grade 3 symptomatic hypokalemia (serum potassium levels <3.0 to 
2.5 mM, NCI-CTCAE version 4.0) or life-threatening hypokalemia with potassium 
levels <2.5 mM (NCI-CTCAE version 4.0, hypokalemia Grade 4), abiraterone acetate treatment 
will be withheld and the subject will be hospitalized for IV potassium replacement and cardiac 
monitoring. Re-initiation of abiraterone acetate treatment after normalization of potassium levels 
must be discussed with and approved by the Sponsor’s medical monitor Table 6.  
Table 6 - Management of Hypokalemia 
 
Serum K+ 
 
Grade of 
Hypokalemia 
 
Action 
 
Further Action or Maintenance 
Low potassium or 
history of 
hypokalemia 
 
Weekly (or more frequent) 
laboratory electrolyte evaluations 
Titrate dose to maintain a serum potassium 
t3.5 mM d5.0 mM (maintenance of subjects 
at t4.0 mM is recommended) 
<3.5 mM to 3.0mM 
Grade 1 or 2 
Initiate oral or IV potassium 
supplementation 
Consider monitoring magnesium 
and replacement if needed 
Titrate dose to maintain a serum potassium 
t3.5 mM to d5.0 mM (maintenance of 
subjects at t4.0 mM is recommended) 
<3.0 mM to 2.5 mM 
Grade 3 
Withhold abiraterone acetate (and 
initiate oral or IV potassium and 
cardiac monitoring 
Consider monitoring magnesium 
and replacement if needed 
Call the Sponsor’s medical monitor prior to 
re-initiating study drug 
<2.5 mM 
Grade 4 
Withhold abiraterone acetate and 
initiate oral or IV potassium and 
cardiac monitoring 
Consider monitoring magnesium 
and replacement if needed 
Call the Sponsor’s medical monitor prior to  
re-initiating study drug 
IV=intravenous; mM=millimolar. 
8.2.3.2 Management of Hypertension 
x 
If Grade 1 or 2 AEs occur, management per investigator. No abiraterone acetate dose 
reduction. 
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x 
If Grade 3 or 4 AEs occur, withhold abiraterone acetate. Adjust or add medications to 
mitigate the toxicity or consider the specific mineralocorticoid receptor blocker, 
eplerenone (the dose not to exceed 200 mg/D). When hypertension resolves to dGrade 1, 
resume study drug at full dose.  
x 
If toxicity recurs, withhold abiraterone acetate, and adjust or add medications to mitigate 
the toxicity. When toxicity resolved to dGrade 1, resume abiraterone acetate with the first 
dose level reduction (3 tablets, 750 mg of study drug). 
x 
If toxicity recurs, withhold abiraterone acetate, and adjust or add medications to mitigate 
the toxicity. When toxicity resolved to dGrade 1, resume abiraterone acetate with the 
second dose level reduction (2 tablets, 500 mg of abiraterone acetate). 
x 
If toxicity recurs despite optimal medical management and the dose reduction, discontinue 
abiraterone acetate. 
8.2.3.3 Management of Fluid Retention/ Edema 
x 
If lower limbs edema occurs, supportive management per investigator. No abiraterone 
acetate dose reduction. 
x 
If Grade 3 pulmonary edema requiring supplemental oxygen occurs, withhold abiraterone 
acetate. Adjust or add medications to mitigate the toxicity and consider the specific 
mineralocorticoid receptor blocker, eplerenone (the dose not to exceed 200 mg/D). When 
toxicity resolves to d Grade 1, resume abiraterone acetate at full dose.  
x 
If toxicity recurs, withhold abiraterone acetate, and adjust or add medications to mitigate 
the toxicity. When toxicity resolved to dGrade 1, resume abiraterone acetate with the first 
dose level reduction (3 tablets, 750 mg of abiraterone acetate). 
x 
If toxicity recurs, withhold abiraterone acetate, and adjust or add medications to mitigate 
the toxicity. When toxicity resolved to dGrade 1, resume abiraterone acetate with the 
second dose level reduction (2 tablets, 500 mg of abiraterone acetate). 
x 
If toxicity recurs despite optimal medical management and the dose reduction, discontinue 
abiraterone acetate. 
8.2.3.4 Management of Abnormal Liver Function Tests 
For patients who develop hepatotoxicity during treatment (alanine aminotransferase [ALT] 
increases or aspartate aminotransferase [AST] increases above 5 times the upper limit of normal 
[ULN]), treatment should be withheld immediately. Re-treatment following return of liver 
function tests to the patient’s baseline may be given at a reduced dose of 500 mg (two tablets) 
once daily. For patients being re-treated, serum transaminases should be monitored at a minimum 
of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the 
reduced dose of 500 mg daily, treatment should be discontinued. If patients develop severe 
hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime while on therapy, 
treatment should be discontinued and patients should not be re-treated. 
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8.4 
BLINDING PROCEDURES 
8.4.1 Methods of blinding 
No blinded central review will be done, however all the images (MRI, CT scan and bone scan) 
will be archived centrally by the vendor in case of discrepancies, unexpected findings or 
regulatory may request a central review. 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
8.5.1 Patient number and treatment number 
Patients who meet all inclusion criteria and none of the exclusion criteria are deemed eligible for 
randomization. 
Randomization and treatment allocation(s) will be performed centrally by an interactive 
voice/Web response system (IVRS/IWRS). A randomized patient is a patient with a patient 
number and a treatment allocated by the IVRS/IWRS. 
8.5.2 Allocation of treatment(s) 
Treatment will be allocated by the IVRS/IWRS to either arm in a 1:1 ratio. 
Randomization will be stratified by:     
x 
Extra nodal visceral metastases (yes, no), 
x 
Level of PSA decline within 12 months of initiation of AR targeted therapy (no decline, 
decline 1% to < 50%, decline 50%). 
x 
Time from AR targeted agent initiation to progression ([0; 6 months], ]6; 12 months] 
8.6 
PACKAGING AND LABELING 
This is an open label study. The Investigational Medicinal Product (cabazitaxel) will be packaged 
in: 
x 
Sterile, single-use vials 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
For infusion conditions, see Section 8.1.1.3 (PVC-free material). 
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8.7 
STORAGE CONDITIONS AND SHELF LIFE 
Cabazitaxel (concentrate for solution for infusion) as packaged should be stored between 15°C 
and 30°C. Do not refrigerate. 
The solvent was also shown to be stable under these conditions. 
All vials must be kept in their box until use. 
Abiraterone acetate and Enzalutamide: refer to the package insert (PI) or the summary of product 
characteristics (SmPC). 
8.8 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
Investigational Medicinal Product (IMP) will be responsible for ensuring that the IMP used in the 
clinical trial is securely maintained as specified by the Sponsor and in accordance with applicable 
regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allows the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.8.1 Treatment accountability and compliance 
The investigator or pharmacist will inventory and acknowledge receipt of all shipments of the 
investigational medicinal product. The study drug must be kept in a locked area with restricted 
access. The study drug must be stored and handled in accordance with the manufacturer's 
instructions. The investigator or pharmacist will also keep accurate records of the quantities of the 
study drugs dispensed and used by each patient. The study monitor will periodically check the 
supplies of study drugs held by the investigator or pharmacist to verify accountability of all study 
drugs used. At the conclusion of the study, all unused study drugs and all medication containers 
will preferably be destroyed at the investigational site (at a locally authorized facility) according 
to local regulation unless other arrangements have been approved by the Sponsor. Destruction of 
unused vials will occur only after drug accountability has been performed and written permission 
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for destruction has been obtained. Used medication vials may be destroyed during the conduct of 
the study as required by the institution.  
The investigator or sub-investigator will supervise administration of the investigational drug. Any 
delegation of this responsibility must follow Section 13.1. 
The person responsible for drug dispensing is required to maintain adequate records of all study 
drugs. These records (eg, drug inventory form) include the date the study medication is received 
from the Sponsor, dispensed for patient, and destroyed or returned to the Sponsor as detailed in  
(Section 8.8.2).  The fixed label portions of all the cabazitaxel vials administered to patients must 
be completed (patient number, date of infusion).  The batch number (PR number) on the vial must 
be recorded on the CRF/drug accountability form.   
The person responsible for drug administration to the patient will record precisely the dose, date, 
and time the drug is administered to the patient. 
8.8.2 Return and/or destruction of treatments 
Partially used cabazitaxel will be destroyed on site according to standard practices of the site. 
Unused cabazitaxel will be destroyed on site after final batch accountability has been validated by 
the sponsor monitoring team representative and only after having received written authorization 
from the sponsor. 
In the event of a potential defect in the quality of Investigational Medicinal Product, it may be 
necessary for the Sponsor to initiate a recall procedure. In this case, the Investigator will be 
responsible for promptly addressing any request made by the Sponsor, in order to recall 
Investigational Medicinal Product and eliminate potential hazards. 
8.9 
CONCOMITANT MEDICATION 
All treatments being taken by the patient within 4 weeks prior to the start of study treatment, or at 
any time during the study and up to 30 days after the end of study treatment in addition to the 
Investigational Medicinal Product are regarded as concomitant treatments and must be 
documented on the appropriate pages of the CRF.  
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the patient's welfare and are unlikely to interfere with the Investigational 
Medicinal Product, they may be given at the discretion of the investigator and recorded in the 
eCRF. 
The following concomitant treatments are not permitted during this study: 
x 
Concurrent treatment with other investigational drugs. 
x 
Concurrent treatment with any other anticancer therapy including immunotherapy, 
targeted therapy or biological therapies.  
Palliative radiotherapy given for pain control is a pain progression criterion (see 
Section 9.2.5.2). Therefore, palliative radiotherapy is not allowed, except if initiated 
within the 12 first weeks after initiation of the study treatment (pain alone within the first 
12 weeks should not be considered as PD).  
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x 
Concurrent treatment with strong inhibitors of cytochrome P450 3A4 ( Appendix G( , such 
as ketoconazole, itraconazole, clarythromycin. For patients who were receiving treatment 
with such agents, a two-week washout period is required prior to randomization. 
x 
Concurrent treatment with potent strong or moderate inducers of cytochrome P450 3A4, 
such as the antiepileptic drugs carbamazepine, phenytoin, phenobarbital, and St John Wort 
(millepertuis) (Appendix G).  For patients who were receiving treatment with such agents, 
a two-week washout period is required prior to randomization.  
x 
Concurrent treatment with CYP2D6 substrates and that have a narrow therapeutic window. 
For patients who were receiving treatment with such agents, a two-week washout period is 
required prior to randomization ( Appendix G). 
x 
Concurrent treatment with strong or moderate inducers or strong inhibitors of CYP2C8. 
For patients who were receiving treatment with such agents, a two-week washout period is 
required prior to randomization  (Appendix G). 
x 
Concurrent treatment with CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow 
therapeutic index. For patients who were receiving treatment with such agents, a two-week 
washout period is required prior to randomization (Appendix G).  
The following concomitant treatments are permitted during this study: 
x 
LH-RH agonists or antagonist that are ongoing prior to study entry. In addition, patients 
who are treated with LH-RH agonists or antagonist (ie, without orchiectomy) should 
continue this therapy during the study treatment period 
x 
The use of bisphosphonates and denosumab are allowed, however the dose must be stable 
for 4 weeks prior to enrollment and during the study treatment period (though 
bisphosphonate or denosumab treatment may be discontinued during the study treatment 
period).  Vitamin D and calcium are allowed to treat osteoporosis. 
x 
Ancillary treatment must be given as medically indicated; they must be specified in the 
CRF. 
x 
Primary prophylactic with G-CSF should be considered in patients with high-risk clinical 
features (age >65 years, poor performance status, previous episodes of febrile neutropenia, 
extensive prior radiation ports, poor nutritional status or other serious comorbidities) 
according to ASCO guidelines (33) and is left to the investigator’s judgment.  
x 
Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte 
replacement if they become dehydrated. Standard antidiarrheal treatments (eg, loperamide) 
are recommended (see Section 8.1.2.3.3.3). 
x 
Supportive treatment as medically indicated for the patient’s well-being (including 
hyperalimentation and blood transfusion) may be prescribed at the investigator’s 
discretion.  Every medication or treatment taken by the patient during the trial and the 
reason for its administration must be recorded on the CRF. 
x 
Use of erythropoietin for chemotherapy-related anemia. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
Radiographic Progression-Free Survival (rPFS) defined as the time from randomization to the 
occurrence of one of the following: 
x 
Radiological tumor progression using RECIST 1.1 (Appendix B).  
x 
Progression of  bone lesions using PCWG2 criteria: 
- 
The first bone scan with 2 new lesions compared to baseline is observed <12 weeks 
from randomization and is confirmed by a second bone scan taken 6 weeks later 
showing 2 additional new lesions compared to week 9 bone scan (a total of 4 new 
lesions compared to baseline); 
- 
The first bone scan with 2 new lesions compared to baseline is observed  12 weeks 
from randomization and the new lesions are verified on the next bone scan 6 weeks 
later (a total of 2 new lesions compared to baseline). 
Lymph nodes that progress but <20 mm in short axis should not be considered as PD. 
x 
Death due to any cause 
9.2 
SECONDARY ENDPOINTS 
The secondary efficacy endpoints will include: 
9.2.1 PSA endpoints 
PSA-derived efficacy endpoints in this study will include PSA response, duration of PSA 
response and Time to PSA progression. For each patient, PSA will be assessed at baseline, every 
3 weeks during study treatment, and in case of study treatment discontinuation without PSA 
progression every 12 weeks until the end of the first further anticancer therapy if any or study cut 
off, whichever comes first. Two PSA determinations are needed to define PSA progression. 
9.2.1.1 PSA response  
PSA response defined as a decline of serum PSA from baseline of 50% confirmed at least 
3 weeks later. It will be calculated among patients with a baseline PSA 10 ng/mL. Increases (of 
any magnitude) in PSA during the first 12 weeks should be ignored in determining PSA response. 
9.2.1.2 Time to PSA progression (TTPP) 
Time to PSA progression is defined as the time interval between the date of randomization and the 
date of first documented PSA progression.  
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PSA progression is defined as (2) (Appendix A):  
x 
Decline from baseline: an increase of 25% (at least 2ng/mL) over the nadir value, 
confirmed by a second PSA value at least 3 weeks apart. 
x 
No decline from baseline: an increase of 25% (at least 2ng/mL) over the baseline value 
after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart. 
Early increase in PSA within 12 weeks, when followed by subsequent decline, is ignored in 
determining this endpoint. Early rise in PSA only indicates progression if it is associated with 
another sign of disease progression or if it continues beyond 12 weeks. Progression will only be 
dated prior to 12 weeks if there is continued increase in PSA beyond that time point or if it was 
associated with another sign of disease progression. 
9.2.2 Progression free survival 
Progression free survival (PFS) will be evaluated from the date of randomization to the date of the 
first documentation of any of the following events:  
x 
Radiological tumor progression using RECIST 1.1.  
x 
Progression of  bone lesions using PCWG2 criteria: 
- 
The first bone scan with 2 new lesions compared to baseline is observed <12 weeks 
from randomization and is confirmed by a second bone scan taken 6 weeks later 
showing 2 additional new lesions compared to week 9 bone scan (a total of 4 new 
lesions compared to baseline); 
- 
The first bone scan with 2 new lesions compared to baseline is observed 12 weeks 
from randomization and the new lesions are verified on the next bone scan 6 weeks 
later (a total of 2 new lesions compared to baseline). 
Lymph nodes that progress but < 20 mm in short axis should not be considered as PD. 
x 
PSA progression, 
x 
Pain progression, 
x 
Or death due to any cause. 
9.2.3 Overall Survival  
The Overall Survival (OS) is defined as the time interval from the date of randomization to the 
date of death due to any cause. 
9.2.4 Tumor endpoints 
9.2.4.1 Tumor response 
Tumor response will be analyzed in patients with measurable disease (RECIST 1.1).  
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Tumor response is defined as either a partial response (PR) or complete response (CR) according 
to the RECIST 1.1 criteria (see Appendix B). 
9.2.4.2 Duration of tumor response 
Duration of tumor response is defined as the time between the first evaluation at which the 
response criteria (PR-CR as per RECIST 1.1) are met and the first documentation of tumor 
progression.  
9.2.5 Pain endpoints 
Diary will be utilized to collect analgesic consumption and pain scores in all patients (Appendix 
E). The Brief Pain Inventory-Short Form (BPI-SF) will be utilized to assess pain). Pain scores 
(WHO Analgesic Ladder and BPI-SF) will be assessed in all patients at baseline, before each 
cycle, at the end of treatment and then every 12 weeks until disease progression, start of another 
anticancer therapy or study cut off, whichever comes first. 
9.2.5.1 Pain response 
Pain response is defined as: 
x 
A decrease by <30% from baseline in the average of BPI-SF pain intensity score observed 
at 2 consecutive evaluations 3 weeks apart without increase in analgesic usage score 
(defined as a 1 point increase on the WHO analgesic scale). 
Either criterion has to be maintained for two consecutive evaluations at least 3 weeks apart.  
Increases in pain during the first 12 weeks should be ignored in determining pain response. 
9.2.5.2 Time to pain progression  
Time to pain progression is defined as the time interval between the date of randomization and the 
date of either first documented pain progression. 
Pain progression is defined as: 
x 
An increase by 30% from baseline in the average of BPI-SF pain intensity score observed 
at 2 consecutive evaluations 3 weeks apart without decrease in analgesic usage score OR 
increase in analgesic usage score of 30% or greater. 
Either criterion has to be maintained for two consecutive evaluations at least 3 weeks apart 
Early rise in pain (within the first 12 weeks) only indicates progression if it is associated with 
another sign of disease progression or if it continues beyond 12 weeks. Progression will only be 
dated prior to 12 weeks if there is continued increase in pain beyond that time point or if it was 
associated with another sign of disease progression. 
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9.2.6 Symptomatic skeletal events 
9.2.6.1 SSE rate 
SSE assessment will be performed by clinical evaluation. Occurrence of SSE is defined as:  
x 
The occurrence of a new symptomatic pathological fracture, or 
x 
The use of external beam radiation to relieve bone pain,or 
x 
The occurence of spinal cord compression, or  
x 
Tumor-related orthopeadic surgical intervention 
SSE is not a criterion of progression. 
9.2.6.2 Time to occurrence of SSE 
Time to SSE is defined as the time interval between the date of randomization and the date of the 
occurrence of the first event defining a SSE, whichever is earlier. For each patient, SSE will be 
assessed at baseline, every 3 weeks during study treatment, and every 12 weeks during follow-up 
until occurrence of first SSE or study cut off, whichever comes first. 
9.2.7 Biomarkers 
Analysis of messenger RNAs including androgen-receptor splice variant 7 messenger RNA 
(AR-V7) at baseline and post-treatment in Circulating Tumor Cells (CTCs). 
Detection of AR-V7 in CTCs from patients with CRPC may be associated with resistance to 
enzalutamide and abiraterone (22). 
9.3 
SAFETY ENDPOINT  
9.3.1 Adverse events 
Treatment-emergent adverse events: Type according to MedDRA (Medical Dictionary for 
Regulatory Activities), frequency, severity according to NCI CTCAE V4.0, seriousness, and 
relationship to study treatment will be assessed. 
Refer to Section 10.4 to Section 10.6 for details. 
9.3.2 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry 
and urinalysis). Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables. 
Laboratory abnormalities will be assessed according to the NCI CTCAE v.4.0. 
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9.3.3 Vital signs 
Vital signs include: blood pressure, heart rate. 
9.3.4 Electrocardiogram variables 
ECG data will be assessed by the Investigator based on the automatic device reading. 
ECG parameters include: normal or abnormal. 
9.4 
 
Additional Exploratory Collaborative End-Points include: 
x 
Analysis of Circulating Tumor Cells (CTCs) phenotypes as well as expression and 
localization of proteins including androgen receptors (AR) isoforms in CTCs at baseline. 
x 
Analysis of tumoral genetic and genomic variations in circulating free nucleic acids 
derived from plasma at baseline, on treatment and post-treatment. Subtractive mutation 
analysis will be performed with germline DNA data to identify tumoral specific variations. 
Special procedure for collection, storage and shipping of samples will be described in the 
laboratory manual. 
9.5 
FUTURE USE OF SAMPLES 
Not all of the blood samples obtained during this study may be used for the tests that are part of 
the clinical trial. Following the conclusion of the study, the samples may be used for additional 
research. This research will help to understand disease subtypes, drug response, and toxicity, and 
possibly to identify new drug targets or biomarkers that predict subject response to treatment. The 
use of the samples for internal research will be done in accordance with the guidelines defined by 
the FDA document “Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using 
Leftover Human Specimens that are Not Individually Identifiable” (issued 25 April 2006) and 
European Medicines Agency’s (EMA’s) “Reflection Paper on Pharmacogenetic Samples, Testing, 
and Data Handling” (EMA 2007). If a subject requests destruction of their blood samples, and the 
samples have not yet been de-identified, the sponsor (or central laboratory) will destroy the 
samples as described in this FDA guidance. The sponsor (or central laboratory) will notify the 
investigator in writing that the samples have been destroyed. 
 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
All patients entering the study must be evaluated according to the schedule outlined in the study 
Flow Chart (see Section 1.2) and described below. The results of the evaluation will be recorded 
on the appropriate eCRF pages until the patients are not followed any longer (End of Study) 
10.1.1 Screening 
Each potential patient will be examined before the start of the study to determine his eligibility for 
participation. These tests are to be performed within 4 weeks prior to study randomization, with 
the exception of physical examination, biological tests, PSA measurement and ECG that must be 
performed no more than 8 days before randomization. If the time between biological baseline 
work-up and first administration of study treatment is more than 8 days, biological tests should be 
done again to check that eligibility criteria are still met. The written informed consent will have to 
be signed by the patient before any protocol specific procedures. 
The following examinations will be performed: 
x 
Inclusion/Exclusion criteria within 8 days prior randomization. 
x 
Demographic characteristics within 4 weeks prior randomization. 
x 
Physical examination within 8 days prior randomization including major body systems 
exam, height and weight, ECOG performance status (PS), and vital signs (blood pressure, 
heart rate). 
x 
Pain assessment and analgesic for cancer pain: diary information should be collected 
within 3 days before first treatment administration using the BPI-SF (Appendix E) and 
WHO Analgesic Ladder (Appendix F). 
x 
Medical, surgical and oncological history including significant prior and concurrent 
illnesses, primary diagnosis and prior antitumor therapy. Renal medical history which 
should include co-morbidities at risk of renal impairment (eg, diabetes) and medication at 
risk of renal function impairment (such as bisphosphonates, non-steroids 
anti-inflammatory drugs, aminoglycosides antibiotics, etc) should be documented within 
4 weeks prior randomization 
x 
Concomitant medications will be recorded from 4 weeks prior to randomization. 
x 
Symptomatic Skeletal Events within 8 days before randomization: The use of external 
beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological 
fracture, or occurrence of spinal cord compression, or tumor-related orthopeadic surgical 
intervention.  
x 
12-lead ECG within 8 days prior randomization 
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x 
Hematology within 8 days prior D1 cycle 1 (time between hematological work-up and 
day 1 cycle 1 should not exceed 8 days; if time exceed 8 days, hematological work-up 
should be repeated): WBC with differential count, hemoglobin, platelet count. To be 
repeated before cycle 1 if the time between baseline biological work-up and first 
administration of study treatment is more than 8 days, to check that eligibility criteria are 
still met. 
x 
Blood Chemistry and Coagulation tests within 8 days prior D1 cycle 1 (time between 
biochemistry work-up and day 1 cycle 1 should not exceed 8 days; if time exceed 8 days, 
biochemistry work-up should be repeated): sodium, potassium, calcium, phosphorus, 
BUN, magnesium, creatinine, total protein, albumin, SGOT (AST), SGPT (ALT), alkaline 
phosphatase, total bilirubin, glucose, lactate deshydrogenase (LDH), and INR . To be 
repeated before cycle 1 if the time between baseline biological work-up and first 
administration of study treatment is more than 8 days, to check that eligibility criteria are 
still met. In addition and only at baseline: serum Chromogranin A (CgA). 
x 
Blood sample for CTCs assay: 3 samples will be taken within 8 days prior randomization 
and 2 of them at least 24h apart before first cycle administration.   
x 
Blood sample for cfDNA/cfRNA/germline assay: 3 samples will be taken within 8 days 
prior randomization and 2 of them at least 24h apart before first cycle administration. 
x 
PSA (last PSA if progression is defined by rising PSA) within 8 days prior randomization: 
in case of rising PSA alone 2 sequential increases above the previous lowest reference 
value obtained at least 1-week apart are required. A PSA value at study entry of at least 
2 ng/mL is required.  
x 
Serum testosterone measurement within 4 weeks prior to randomization 
x 
Tumor assessment within 4 weeks prior to randomization (6 weeks for bone scan): whole 
body (abdominal/pelvic/chest) CT-Scan or MRI, bone scan and all other exams as 
clinically indicated (eg, brain CT-Scan or MRI in case of clinical suspicion of central 
nervous system involvement) to assess all TARGET or NON TARGET lesions 
(measurable and non-measurable). CT-Scan/MRI will be preferred to X-Ray for the 
purposes of efficacy assessment. To ensure comparability, the imaging should be 
performed using identical techniques throughout the study period (ie, CT-scan or MRI, 
scans performed immediately following bolus contrast administration using a standard 
volume of contrast, the identical contrast agent, and preferably the same scanner). When 
available, spiral CT acquisition should be done. Slice thickness should be adapted to the 
anatomical area and presumed size of the lesions. Slice thickness of 5 to 8 mm should be 
favored rather than 10 mm, especially during spiral acquisition. 
If limitations appear in volume acquisition, it is encouraged to choose a 1.5 pitch and thin slices, 
rather than a 1 pitch with thick slices. A centimeter scale should appear on films.  
x 
Other investigations if clinically indicated. 
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10.1.2 Randomization 
Randomization will take place once the consented patient has completed all the necessary 
screening procedures and is deemed eligible for study entry by the investigator or designee. All 
eligible patients must be randomized by contacting the IVRS/IWRS (see Section 8.5). 
The results of the screening examinations will be recorded in each randomized patient’s CRF. 
Source documentation to support the screening results must be maintained in the patient’s medical 
record. Treatment should begin within 7 days after randomization. 
10.1.3 During study treatment  
x 
Physical examination before each cycle including major body systems exam, weight, 
ECOG performance status (PS), and vital signs (blood pressure, heart rate). 
x 
Adverse events assessment: at each cycle 
x 
Pain assessment and analgesic for cancer pain: diary information should be collected 
using the BPI-SF (Appendix E) and WHO Analgesic Ladder at D1 prior each cycle 
(Appendix F).  
x 
Symptomatic Skeletal events: Assessment will be done at each cycle. The use of external 
beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological 
fracture, or occurrence of spinal cord compression, or tumor-related orthopeadic surgical 
intervention. 
x 
Concomitant medications will be recorded at every cycle. 
x 
Hematology will be done before each study treatment administration (-3 days window is 
allowed) and in case of fever or infection: WBC with differential count, hemoglobin, 
platelet count.  
In addition, hematology will be performed every week (D8 and D15) during the 3 first 
cycles (+/- 1 day window is allowed) and then within further cycles in case of fever or 
infection. 
x 
Blood Chemistry will be done before each study treatment administration (-3 days 
window is allowed): sodium, potassium, calcium, phosphorus, BUN, magnesium, 
creatinine, total protein, albumin, SGOT (AST), SGPT (ALT), alkaline phosphatase, total 
bilirubin, glucose, LDH.  
In addition, blood chemistry (sodium, potassium, calcium, BUN, magnesium, creatinine, 
SGOT (AST), SGPT (ALT), total bilirubin) will be performed every week (D8 and D15) 
during the 3 first cycles (+/-1 day window is allowed). 
x 
Patient’s diary to be used by all patients to record the consumption of abiraterone acetate 
or enzalutamide (in Arm B) and/or prednisone or prednisolone. 
x 
Blood sample for cfDNA/cfRNA assay: 1 sample will be taken at C4D1. 
x 
PSA: before each next cycle. 
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x 
Tumor assessment every 9 weeks after first study treatment administration for the first 
6 months (27 weeks) and then every 12 weeks: whole body (abdominal/pelvic/chest) 
CT-Scan or MRI, bone scan and all other exams as clinically indicated (eg, brain CT-Scan 
or MRI in case of clinical suspicion of central nervous system involvement) to assess all 
TARGET or NON TARGET lesions should be assessed. To ensure comparability, the 
imaging should be performed using identical techniques throughout the study period 
(ie, scans performed immediately following bolus contrast administration using a standard 
volume of contrast, the identical contrast agent, and preferably the same scanner). 
x 
Other investigations if clinically indicated 
10.1.4 End of treatment 
All patients must continue to be observed for at least 30 days after the final dose of study 
treatment. The following procedures should be performed within the 22-30 days following the 
final dose of study treatment: 
x 
Physical exam: 
ECOG PS, weight, examination of major body systems, including vital signs (blood 
pressure, heart rate). 
x 
12-lead ECG only if clinically indicated or cardiac event during the treatment period. 
x 
Adverse events assessments. 
x 
Pain assessment and analgesic for cancer pain(Appendix E)( Appendix F). 
x 
Symptomatic Skeletal events: The use of external beam radiation to relieve bone pain, or 
occurrence of a new symptomatic pathological fracture, or occurrence of spinal cord 
compression, or tumor-related orthopeadic surgical intervention. 
x 
Hematology: WBC with differential count, hemoglobin, platelet count. 
x 
Blood Chemistry: sodium, potassium, calcium, phosphorus, BUN, magnesium, 
creatinine, total protein, albumin, SGOT (AST), SGPT (ALT), alkaline phosphatase, total 
bilirubin, glucose, LDH.  
x 
Blood sample for CTCs assay: 1 sample will be taken at relapse or EOT 
x 
Blood sample for cfDNA/cfRNA assay: 1 sample will be taken at relapse or EOT 
x 
Concomitant medications assessments 
x 
PSA 
x 
Tumor assessment, if end of treatment visit occurs at the time of a planned tumor 
assessment: 
whole body (abdominal/pelvic/chest) CT-Scan or MRI, bone scan and all other exams as 
clinically indicated (eg, brain CT-Scan or MRI in case of clinical suspicion of central 
nervous system involvement) to assess all TARGET or NON TARGET lesions 
(measurable and non-measurable). 
x 
Other investigations if clinically indicated 
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10.1.5 Follow-up period 
All patients will be followed every 12 weeks (after end of treatment visit) until death, cut-off date, 
or withdrawal of patients’consent whichever comes first: 
x 
Survival status 
x 
ECOG PS, weight until disease progression, start of another anticancer therapy or cut-off 
date, whichever comes first. 
x 
All serious adverse events and/or related to study treatment adverse events ongoing at the 
end of the study, or new related to study treatment adverse event which occur during the 
follow-up period will be recorded until recovery, or stabilization of patient’s condition. 
x 
Concomitant medications if correspond to treatment of related adverse events. 
x 
Pain and analgesic for cancer pain: until disease progression, start of another anticancer 
therapy or cut-off date, whichever comes first. The diary information should be collected 
at each scheduled visit. 
x 
Symptomatic Skeletal events: The use of external beam radiation to relieve bone pain, or 
occurrence of a new symptomatic pathological fracture, or occurrence of spinal cord 
compression, or tumor-related orthopeadic surgical intervention, until the occurrence of 
first SSE or study cut-off date, whichever comes first. 
x 
PSA: until the end of the first further anticancer therapy if any or the study cut-off date, 
whichever comes first. 
x 
Tumor assessment until radiological PD, start of another anticancer therapy or study cut-
off if patient discontinued study treatment without radiological progressive disease:  
whole body (abdominal/pelvic/chest) CT-Scan or MRI, bone scan and all other exams as 
clinically indicated (eg, brain CT-Scan or MRI in case of clinical suspicion of central 
nervous system involvement) to assess all TARGET or NON TARGET lesions should be 
assessed. To ensure comparability, the imaging should be performed using identical 
techniques throughout the study period (ie, scans performed immediately following bolus 
contrast administration using a standard volume of contrast, the identical contrast agent, 
and preferably the same scanner). 
x 
Further anticancer therapy if any, which is at the discretion of the investigator. In case 
of patient discontinues study treatment due to reason other than progressive disease, 
further anticancer therapy will not be initiated before progression is documented. In case it 
occurs within the 4 first cycles, initiation or not of further anticancer therapy before 
radiographic progression is documented, is left to the investigator decision. Data related to 
the first further anticancer therapy response will be collected. 
10.1.6 Post study cut-off date 
Patients still on study treatment at the cut-off date can continue study treatment until at least 1 
treatment permanent discontinuation criterion as defined in Section 10.3.2 is met. The following 
information will be collected during the study treatment administration:  
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x 
IMP administration 
x 
All serious adverse events regardless of relationship to study treatment and adverse events 
considered related to study treatment.  
x 
End of treatment reason.  
x 
No follow-up information will be collected after these patients discontinue study treatment 
except all serious adverse events still ongoing at the end of study treatment and all adverse 
events considered as related to study treatment still ongoing or occurring after the end of 
study treatment, which will be followed until resolution/stabilization. 
10.2 
DEFINITION OF SOURCE DATA 
Source data includes all information in original records and certified copies of original records of 
clinical findings, observations, or other activities necessary for the reconstruction and evaluation 
of the trial. Source data are contained in source documents. 
Source documents are original documents, data and records (eg, hospital records, clinical and 
office charts, laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcripts certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, X-rays, patient files, and records kept at the pharmacy, at the laboratories, and at 
medical-technical departments) involved in the clinical study. Source documentation must be 
maintained to support information provided within a CRF. 
The results of certain examinations or evaluations recorded in the CRF may be considered to be 
source data (such as patient’s BPI-SF, WHO Analgesic Ladder) 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the CRF. In any case, the 
patient should remain in the study as long as possible. 
Patients will be followed up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the IP. 
All permanent treatment discontinuation should be recorded by the Investigator in the appropriate 
pages when considered as confirmed. 
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10.3.1 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
10.3.2 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the eCRF. 
x 
The patients may withdraw from treatment if they decide to do so, at any time and 
irrespective of the reason or at the request of their legally authorized representative. 
“Legally authorized representative” means an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective patient to the 
patient’s participation in the procedure(s) involved in the research. 
x 
If, in the investigator’s opinion, continuation of the treatment would be detrimental to the 
patient’s well-being, such as: 
- 
Radiographic disease progression as defined in Section 9.1,  
- 
Unacceptable adverse event(s) not manageable by symptomatic therapy, dose delay or 
dose modification (see Section 8.1), 
- 
Intercurrent illness that prevents further administration of study treatment, 
- 
Non-compliance to the study protocol or logistic consideration. 
x 
Patient is lost to follow-up. 
In all cases, the reason for and date of withdrawal must be recorded in the eCRF and in the 
patient's medical records. The patient must be followed up to establish whether the reason was an 
adverse event, and, if so, this must be reported in accordance with the procedures in Section 10.4. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation after 24 hours for making a decision of permanent discontinuation of the IMP for the 
concerned patient.   
10.3.3 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the IMP.  
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. 
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10.3.4 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. 
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who fail to return to the site for the EOT visit, unless the patient withdraws the 
consent for follow-up, the Investigator should make the best effort to recontact the patient 
(eg, contacting patient’s family or private physician, reviewing available registries or health care 
databases), and to determine his/her health status, including at least his/her vital status. Attempts 
to contact such patients must be documented in the patient’s records (eg, times and dates of 
attempted telephone contact, receipt for sending a registered letter).    
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused. 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
10.4.1.2 Serious adverse event 
SAE is any untoward medical occurrence that at any dose: 
x 
Results in death, or 
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x 
Is life-threatening, or; 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe. 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
x 
Results in persistent or significant disability/incapacity, or 
x 
Is a congenital anomaly/birth defect 
x 
Is a medically important event: 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for determining 
which condition has to be considered as a medically important event. The list is not intended to be 
exhaustive: 
x 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study (only if judged 
unusual/significant by the Investigators in oncology studies) 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically 
the effect of a study drug on these diseases). 
10.4.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
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further investigation in order to characterize and understand them. Adverse events of special 
interest may be added or removed during a study by protocol amendment. 
x 
Pregnancy occurring in a female partner of a male subject entered in a study with 
IMP/NIMP;  
- 
Pregnancy occurring in a female partner of a male patient entered in the clinical trial. It 
will be qualified as an SAE only if it fulfills one of the seriousness criteria (see 
Section 10.4.1.2). 
- 
Follow-up of the pregnancy is mandatory until the outcome has been determined. 
Additional follow-up information may be requested about the baby until at least one 
year after the birth of the baby. 
x 
Symptomatic overdose (serious or non-serious) with IMP/NIMP 
An overdose (accidental or intentional) with the IMP is an event suspected by the Investigator or 
spontaneously notified by the patient and defined as increase of at least 30% of the highest dose of 
cabazitaxel (ie, 30% of 25 mg/m²) to be administered. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
10.4.2 General guidelines for reporting adverse events 
x 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the CRF. 
x 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s).  
x 
The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
x 
When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
x 
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or 
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10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
x 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
x 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
x 
All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 
x 
A back-up plan (using a paper CRF process) is available and should be used when the e 
CRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest   
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the eCRF. Obligations of the 
Sponsor 
During the course of the study, the Sponsor will report in an expedited manner: 
x 
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, IECs/IRBs as appropriate and to the Investigators.    
x 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected (20). 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
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10.5 
SAFETY INSTRUCTIONS 
10.5.1 Physical examination 
Physical examination will include, but not limited to the examination of major body systems: 
x 
Vital signs (blood pressure, heart rate), 
x 
Height (screening only), body weight, 
x 
ECOG performance status (Appendix C).  
If abnormal findings emerge or worsen or become serious from the baseline assessment, then the 
adverse event page of the CRF should be completed for these findings. If a finding meets the 
criteria for a serious adverse event, then the appropriate procedures for reporting such events 
should be followed as described in Section 10.4.3.  Height will be recorded at baseline only. Body 
weight and ECOG PS will be recorded at baseline, prior to the start of each treatment cycle (every 
3 weeks) and every follow up visit (every 12 weeks) until death or cut-off date whichever comes 
first.  
Every attempt should be made to have the same study personnel to perform the assessment 
throughout the study for any given patient for consistency of grading. 
10.5.2 Laboratory variables 
Hematology panel and blood chemistry profile will be performed by a local laboratory. Baseline 
results must be available for eligibility determination. At the start of each new treatment cycle, 
results must be available prior to treating the patient with the study drug. In addition, 
hematological test will be performed every week (D8 and D15) during the 3 first cycles and then 
within further cycles only in case of fever or infection.  
10.6 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
 
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11 
STATISTICAL CONSIDERATIONS 
The material of Section 11 of the Clinical Trial Protocol is the basis for the Statistical Analysis 
Plan (SAP) for the study. This plan may be revised during the study to accommodate Clinical 
Trial Protocol amendments and to make changes to adapt to unexpected issues in study execution 
and data that affect planned analyses. 
11.1 
 
Based on bibliographic references (6)(7)(8)(9)(10), a Hazard Ratio of 0.67 is targeted as the 
smallest effect of clinical interest. The following table presents how such a HR translates for a 
variety of envisaged median rPFS in the abiraterone acetate or Enzalutamide group (11)(12). 
 
Hazard Ratio 
Median rPFS (month) 
 
abiraterone acetate or Enzalutamide group 
Cabazitaxel group 
 
 
 
0.67 
4 
6.0 
0.67 
5 
7.5 
0.67 
6 
9.0 
 
A total of 155 patients with event are needed to achieve 80% power to demonstrate rPFS 
superiority of Cabazitaxel over abiraterone acetate or Enzalutamide by one-sided log rank test at 
0.05 type I error rate. Further assuming the accrual is at a constant rate of 4 patients per month for 
5 months and then 11 patients per month, a total of 206 patients in 2 arms (103 patients per arm) 
is anticipated to be needed to reach the targeted number of patients with event. 
Calculations were made using East 6.2 software. 
11.2 
DISPOSITION OF PATIENTS 
The total number of patients for each of the following categories will be provided into a summary 
table: 
x 
Intent to Treat (ITT) patients 
x 
Safety population patients 
x 
Evaluable patients 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population.   
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For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
Screened patients are defined as patients who meet the inclusion criteria.  
Allocation of randomized treatment to eligible patients (patients who meet all inclusion/exclusion 
criteria) will be centrally performed using an IVRS/IWRS. A patient is considered as randomized 
as soon as there is confirmation of successful allocation of a randomization number through the 
IVRS/IWRS. 
Patients allocated outside the IVRS/IWRS will not be taken into account in any of the analyses. 
11.3.1 Efficacy populations 
11.3.1.1 Intent–to-treat population 
The primary efficacy population is the Intent-To-Treat (ITT) population which includes all 
randomized patients. The patients will be analyzed in the treatment group to which they will be 
allocated by the IVRS/IWRS (ie, “as randomized” regardless of treatment actually received). 
11.3.1.2 Evaluable populations 
The following evaluable patient populations are defined for some selected efficacy endpoints.  
x 
Tumor response will be evaluated in patients with measurable disease at baseline, with at 
least one post baseline assessment. 
x 
PSA response will be evaluated in patients with PSA level >10 ng/dL at baseline, with at 
least one post baseline assessment. 
x 
Pain response will be evaluated in patients using BPI-SF score and WHO Analgesic 
Ladder at baseline, with at least one post baseline assessment. 
Those populations are subsets of the ITT population, and patients are considered in the group “as 
randomized”. 
11.3.2 Safety population 
This population includes all patients who receive at least one dose (either full or partial dose) of 
the study drug. This population is for all Safety analyses. All analyses using this population will 
be based on the treatment actually received (ie, “as treated”). 
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In addition:  
x 
Non randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
x 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
x 
For patients receiving more than 1 study treatment during the trial, as soon as a patient will 
receive any study drug injection of Cabazitaxel, he/she is considered as a Cabazitaxel 
treated patient. 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure 
Extent of exposure will be assessed on the Safety population as follows: 
Number of patients treated, number of cycles administered, duration of dosing (weeks), 
cumulative dose (mg/m²), dose intensity (mg/m²/3 weeks) and relative dose intensity (%) will be 
summarized. 
Dose delays and dose reductions will also be analyzed. 
Further details of the statistical evaluation of the extent of exposure will be provided in the SAP. 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
Primary analysis will consist of rPFS comparison between abiraterone acetate or enzalutamide 
group and Cabazitaxel group through a one-sided 5% log-rank test adjusted for the stratification 
factors (extra nodal visceral metastases, level of PSA decline and time from AR targeted agent 
initiation to progression) as specified at the time of randomization. This analysis will be 
performed on the ITT population. If radiological progression or death is not observed during the 
study, data on rPFS will be censored at the date patient is known to be alive or at the cut-off date, 
whichever comes first. 
The primary Efficacy endpoint will also be analyzed (secondary analyses) as follows: 
The estimates of the hazard ratio and corresponding 90 and 95% confidence interval will be 
provided using a Cox proportional hazard model stratified by the same stratification factors as 
those described above. 
Hazard ratios will also be provided on the subpopulations defined by the stratification factors. 
The survival curves will be estimated using Kaplan-Meier estimates. Median survival times and 
associated 95% confidence intervals will also be provided by treatment. 
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Finally, the 2 arms will also be compared (sensitivity analysis) using a one-sided 5% un-stratified 
log-rank test. 
11.4.2.2 Analyses of secondary efficacy endpoints 
Time To event endpoints will be compared between the 2 treatment arms using the same 
methodology as the primary efficacy endpoint primary analysis. 
The survival curves will be estimated using Kaplan-Meier estimates. Median times and associated 
95% confidence intervals will also be provided by treatment. 
Hazard ratios and 95% confidence intervals will be provided using a Cox proportional hazard 
model. 
Continuous data will be summarized using number of available data, mean, standard deviation, 
median, minimum, Q1, Q3 and maximum for each dose level. The 2 arms will be compared using 
either t-test or non-parametric Mann-Whitney U test (depending on the Normality of the data, the 
SAP will detail which method will be used). 
Categorical data will be summarized using number and percentage of patients in each dose level 
(patients with missing data will not be included in the percentage calculation). The 2 arms will be 
compared using chi-square test. Tumor, PSA, and pain response will be analyzed on their 
respective evaluable population. 
11.4.2.3 Multiplicity considerations 
Not applicable. 
11.4.3 Analyses of safety data 
The summary of Safety results will be presented by treatment group (abiraterone acetate and 
Enzalutamide will also be presented separately). Analysis of adverse events and laboratory data 
will be descriptive and conducted on the Safety population. Summary of safety data will also be 
performed by patient and by cycle. For each of the Safety parameters, a baseline value will be 
defined as the last value or measurement taken up to the first dose in the study. Similar analysis 
will be presented for serious adverse events and adverse events that cause dose reduction, dose 
relay and treatment discontinuation.  
Adverse events will be considered as treatment-emergent if they first occur or worsen after the 
first day of dosing and up to 30 days after the last administration of study drug. 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), High level group term (HLGT), High level term (HLT) and 
preferred term (PT) sorted in alphabetical order for each treatment group, the number (n) and 
percentage (%) of patients experiencing an AE.  Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the safety population within each treatment group. 
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The grade and cycle will be taken into account in the summary. For patients with multiple 
occurrences of the same event, the maximum grade is used. The denominator used for the 
summary by cycle is the total number of cycles administered in a treatment group. For a given 
event, a patient contributes 1 to the numerator for each cycle in which an episode occurred (ie, if 
the date of onset is on or after the first day of the cycle, but prior to the first day of the next cycle).  
The following deaths summaries will be generated: 
x 
Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population by treatment received, 
x 
Death in non-randomized patients or randomized and not treated patients, 
x 
TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) and related TEAEs leading to death by primary SOC, HLGT, HLT and PT 
showing number (%) of patients sorted by internationally agreed order of SOC and 
alphabetic order of HLGT, HLT, and PT. 
x 
All TEAEs leading to death and related TEAEs leading to death will be also summarized 
in one table. This table will include a tabular summary of all TEAEs leading to death with 
a column for the related TEAEs leading to death. 
Hematological toxicities will be assessed from laboratory parameters. Worst NCI CTCAE grades 
of leukopenia, neutropenia, thrombocytopenia, and anemia will be calculated according to the 
NCI common terminology criteria. 
Qualitative and quantitative results will be summarized for hematological toxicities. Qualitative 
data (worst NCI CTCAE grade) will be summarized by cycle and by patient.  
Biochemistry will be analyzed using the worst NCI CTCAE grade, whenever applicable 
(laboratory normal ranges, otherwise) calculated from laboratory values. 
11.4.4 Analyses of Pharmacogenetic variables 
NA 
11.5 
INTERIM ANALYSIS 
NA 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the ICH guidelines for good clinical practice (GCP), all applicable laws, rules 
and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
The informed consent form used by the Investigator for obtaining the patient's informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate Ethics 
Committee (IRB/IEC) for approval/favorable opinion. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party  a 
copy of the written and dated approval/favorable opinion signed by the Chairman with  IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
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possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s Brochure will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
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personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records  which support the data on the CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
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The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
x 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
x 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
x 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
x 
The information on the product leads to doubt as to the benefit/risk ratio; 
x 
Patient enrollment is unsatisfactory; 
x 
The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
x 
Non-compliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP; 
x 
The total number of patients are included earlier than expected; 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication.  In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 90 
days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol.   
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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33. Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of ASCO guideline 
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