A Randomized, Double Blind, Multicenter, Parallel-group, Phase III Study to Evaluate Efficacy and Safety of DCVAC/PCa Versus Placebo in Men With Metastatic Castration Resistant Prostate Cancer Eligible for 1st Line Chemotherapy
Phase: PHASE3
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: SOTIO a.s.

 
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Clinical Development 
 
 
 
DCVAC/PCa 
 
 
Clinical Trial Protocol SP005  
 
 
A Randomized, Double Blind, Multicenter, Parallel-Group, 
Phase III Study to Evaluate Efficacy and Safety of DCVAC/PCa 
Versus Placebo in Men with Metastatic Castration Resistant 
Prostate Cancer Eligible for 1st Line Chemotherapy 
 
 
 
Document type 
Clinical Trial Protocol for Oncology 
EudraCT / IND number 
EudraCT 2012-002814-38 / IND 015255 
Version number 
V07.0 
Development phase 
III 
Document status 
Final 
Date 
08Mar2018 
 
 
 
Property of SOTIO a.s. 
 
Jankovcova 1518/2 
170 00 Prague 7 
Czech Republic 
 
(Hereinafter referred to as “Sponsor or SOTIO”) 
 
 
 
CONFIDENTIAL 
This document contains proprietary information and trade secrets of SOTIO. This information may not be used, 
divulged, published, copied or otherwise disclosed to any third party without the prior written consent of SOTIO. 
 
 
 

 

 
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Declaration by the Investigator 
 
I have read this protocol and agree that it contains all the necessary details for carrying out this study. I will conduct 
the study as described and will complete the study within the time designated. I verify that I am suitably qualified 
by education, scientific medical training and experience to conduct the study. Documentation of my qualifications 
and professional affiliations are contained in my up-to-date curriculum vitae. 
I will provide the supplied copies of the protocol and all information relating to pre-clinical and prior clinical 
experience (e.g. Investigator’s Brochure) to all staff in my unit who participate in this study. I will discuss this 
material with them to ensure that they are fully conversant with medical treatment and the conduct of the study, 
and that they will handle the data and information generated in the study confidentially. 
I will conduct the study in accordance with Good Clinical Practice, the Declaration of Helsinki, the study protocol 
and the moral, ethical and scientific principles that justify medical research. The study will be conducted in 
accordance with the relevant laws and regulations relating to clinical studies and the protection of subjects of the 
country in which the study will be performed. All subjects will be informed comprehensively about the nature of 
the study and will give their written consent to participate before entry into the study. They will be informed that 
they may withdraw from the study at any time. I will use only an information sheet and consent form approved by 
SOTIO and the Independent Ethics Committee (IEC)/ Institutional Review Board (IRB) which has reviewed this 
study. I will supply SOTIO with any material written by myself (e.g. summary of study) which is given to the EC 
in support of the application. 
Where applicable and required the information contained in the case report forms will be transcribed from my 
records, reports and manuscripts. The case report form may be the original source document for certain items. 
Either I or an appointed person will attest to the authenticity of the data and accuracy and completeness of the 
transcription by signing the case report form. I agree to the audit and monitoring procedures that involve 
verification of study records against the original records by direct access. Should it be requested by government 
regulatory agencies, I will make available additional background data from my records, and where allowed from 
the hospital or institution where the study was conducted. I certify that any laboratory, excluding the central 
laboratory(s) appointed for the study in which laboratory parameters will be determined is subject to regular 
external quality control. 
I understand that the case report forms and other data pertinent to this study are the property of SOTIO and are 
confidential. I will supply SOTIO with the study data in such a way that the subject normally cannot be personally 
identified. 
I consent to SOTIO’s and CRO’s collection, processing, transfer, use and storing of my personal data and details 
relating to my professional activities for the purposes of the study. 
I understand that the study may be terminated or enrolment suspended at any time by the Sponsor, with or without 
cause, or by me if it becomes necessary to protect the best interests of the study subjects. 
 
Investigator Signature:  
__________________________________________________ 
 
Date: 
 
 
 
__________________________________________________ 
 
Print Name: 
 
 
__________________________________________________ 
 
Address: 
 
 
__________________________________________________ 
 
Telephone Number: 
 
__________________________________________________ 
 
 
OTHER CONTACT INFORMATION: 
 
Full contact details for each Investigational site, the Sponsor, and key coordinating and operational personnel 
involved in this clinical trial will be maintained in the Trial Master File and in each Site Study File. 

 
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TABLE OF CONTENTS 
ABBREVIATIONS .................................................................................................................................. 9 
ONCOLOGY CLINICAL STUDY PROTOCOL SYNOPSIS .............................................................. 14 
1 BACKGROUND .............................................................................................................................. 21 
1.1 OVERVIEW OF PROSTATE CANCER ............................................................................................ 21 
1.2 IMMUNOTHERAPY IN PROSTATE CANCER ................................................................................. 22 
1.3 OVERVIEW OF DCVAC/PCA ...................................................................................................... 22 
1.3.1 PRE-CLINICAL DEVELOPMENT .................................................................................................... 23 
1.3.2 CLINICAL DEVELOPMENT ........................................................................................................... 23 
1.4 OVERVIEW OF STANDARD OF CARE THERAPIES IN MCRPC .................................................... 27 
1.5 HISTORY OF AMENDMENTS ......................................................................................................... 27 
2 STUDY RATIONALE/PURPOSE .................................................................................................. 30 
2.1 RATIONALE FOR CHEMO-IMMUNOTHERAPY ............................................................................. 30 
3 OBJECTIVES .................................................................................................................................. 33 
3.1 STUDY OBJECTIVES ..................................................................................................................... 33 
3.2 STUDY ENDPOINTS ....................................................................................................................... 33 
3.2.1 PRIMARY EFFICACY ENDPOINT .................................................................................................. 33 
3.2.2 SECONDARY EFFICACY ENDPOINTS ........................................................................................... 33 
3.2.3 SAFETY ENDPOINTS .................................................................................................................... 34 
3.2.4 EXPLORATORY ENDPOINTS ........................................................................................................ 34 
4 STUDY DESIGN ............................................................................................................................. 35 
5 POPULATION ................................................................................................................................. 37 
5.1 INCLUSION/EXCLUSION CRITERIA ............................................................................................. 37 
5.1.1 INCLUSION CRITERIA .................................................................................................................. 37 
5.1.2 EXCLUSION CRITERIA ................................................................................................................. 38 
6 TREATMENTS ............................................................................................................................... 40 
6.1 DESCRIPTION OF TREATMENTS .................................................................................................. 40 
6.1.1 STUDY DRUG/PLACEBO .............................................................................................................. 40 
6.1.2 STANDARD OF CARE THERAPIES ................................................................................................ 40 
6.2 HOW THE STUDY DRUG IS SUPPLIED .......................................................................................... 41 
6.2.1 STUDY DRUG/PLACEBO .............................................................................................................. 41 

 
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6.2.2 STANDARD OF CARE THERAPIES ................................................................................................ 42 
6.3 STORAGE, PREPARATION AND ADMINISTRATION ..................................................................... 42 
6.3.1 DCVAC/PCA / PLACEBO ............................................................................................................ 42 
6.3.2 STUDY DRUG INJECTION SITES .................................................................................................. 42 
6.3.3 STANDARD OF CARE THERAPIES ................................................................................................ 42 
6.4 PATIENT NUMBERING .................................................................................................................. 43 
6.5 TREATMENT ASSIGNMENT .......................................................................................................... 43 
6.6 TREATMENT BLINDING ............................................................................................................... 43 
6.7 PATIENT TREATMENT SEQUENCE .............................................................................................. 44 
6.7.1 SCREEN/RANDOMIZE .................................................................................................................. 44 
6.7.2 SCHEDULE LEUKAPHERESIS PROCEDURE ................................................................................... 44 
6.7.3 THE LEUKAPHERESIS PROCEDURE ............................................................................................. 45 
6.7.4 TREATMENT WITH STANDARD OF CARE CHEMOTHERAPY PLUS DCVAC/PCA OR PLACEBO AND 
CONSEQUENTLY WITH DCVAC/PCA OR PLACEBO ALONE .................................................................... 45 
6.8 ANCILLARY TREATMENTS .......................................................................................................... 46 
6.8.1 ANDROGEN DEPRIVATION THERAPY .......................................................................................... 46 
6.8.2 RESCUE MEDICATION ................................................................................................................. 46 
6.8.3 OTHER CONCOMITANT MEDICATIONS ........................................................................................ 46 
6.8.4 PROHIBITED MEDICATIONS ........................................................................................................ 46 
6.9 PERMITTED DOSING MODIFICATIONS........................................................................................ 47 
6.10 STUDY DRUG DISCONTINUATION/END OF TREATMENT .......................................................... 47 
6.11 FOLLOW-UP FOR TOXICITIES .................................................................................................... 48 
6.12 FOLLOW-UP FOR SURVIVAL ...................................................................................................... 48 
6.13 PREMATURE PATIENT WITHDRAWAL / END OF STUDY ........................................................... 48 
6.14 EMERGENCY UNBLINDING OF TREATMENT ASSIGNMENT ....................................................... 49 
7 VISIT SCHEDULE AND ASSESSMENTS ................................................................................... 50 
7.1 PATIENT DEMOGRAPHICS/OTHER BASELINE CHARACTERISTICS ........................................... 55 
7.2 TREATMENTS ............................................................................................................................... 56 
7.3 EFFICACY ..................................................................................................................................... 56 
7.3.1 PROSTATE-SPECIFIC ANTIGEN .................................................................................................... 56 
7.3.2 SOFT TISSUE AND BONE LESIONS .............................................................................................. 57 
7.3.2.1 SCHEDULE OF IMAGING TIME POINTS ..................................................................................... 57 
7.3.3 SKELETAL RELATED EVENTS ...................................................................................................... 60 
7.4 DISCONTINUATION OF FIRST LINE CHEMOTHERAPY ................................................................. 60 
7.5 DISEASE PROGRESSION ................................................................................................................ 60 
7.6 SAFETY.......................................................................................................................................... 61 
7.6.1 ADVERSE EVENTS ....................................................................................................................... 61 
7.6.2 PHYSICAL EXAMINATION, WEIGHT, HEIGHT ............................................................................... 64 
7.6.3 VITAL SIGNS ............................................................................................................................... 64 
7.6.4 PERFORMANCE STATUS .............................................................................................................. 64 
7.6.5 LABORATORY EVALUATIONS ..................................................................................................... 65 
7.6.6 PREGNANCY ............................................................................................................................... 67 
7.6.7 RADIOLOGICAL EXAMINATIONS ................................................................................................. 67 
7.6.8 HIV, HTLV, SYPHILIS, HEPATITIS B AND C .............................................................................. 67 
7.6.9 CARDIAC EXAMINATIONS ........................................................................................................... 68 
7.7 PATIENT-REPORTED OUTCOMES ............................................................................................... 68 
7.8 PHARMACOKINETICS ................................................................................................................... 68 

 
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7.9 BIOMARKERS ................................................................................................................................ 68 
7.10 EXPLORATORY STUDIES FOR SEARCH OF POTENTIAL BIOMARKERS ..................................... 68 
8 SAFETY MONITORING ................................................................................................................ 70 
8.1 SERIOUS ADVERSE EVENT REPORTING ....................................................................................... 70 
8.1.1   SERIOUS ADVERSE EVENTS RELATED TO DISEASE PROGRESSION ............................................ 71 
8.1.2  ADVERSE EVENTS OF SPECIAL INTEREST .................................................................................. 71 
8.1.3  PREGNANCIES ............................................................................................................................ 71 
8.2 INDEPENDENT DATA MONITORING COMMITTEE ...................................................................... 72 
9 DATA REVIEW AND DATA MANAGEMENT ........................................................................... 73 
9.1 SITE MONITORING ....................................................................................................................... 73 
9.2 DATA COLLECTION ...................................................................................................................... 73 
9.3 DATABASE MANAGEMENT AND QUALITY CONTROL ................................................................ 73 
10 STATISTICAL METHODS AND DATA ANALYSIS ................................................................ 75 
10.1 ANALYSIS POPULATIONS ........................................................................................................... 75 
10.1.1 PATIENT DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ..................................... 76 
10.1.2 TREATMENTS ............................................................................................................................ 76 
10.2 PRIMARY EFFICACY ANALYSIS ................................................................................................. 76 
10.2.1 PRIMARY EFFICACY ENDPOINT ................................................................................................ 76 
10.2.2 STATISTICAL HYPOTHESIS, MODEL AND METHOD OF ANALYSIS ............................................ 76 
10.2.3 SUPPORTIVE ANALYSIS ............................................................................................................ 78 
10.3 SECONDARY OBJECTIVES .......................................................................................................... 78 
10.3.1 SECONDARY EFFICACY ENDPOINTS ......................................................................................... 78 
10.3.2 SAFETY ..................................................................................................................................... 79 
10.4 EXPLORATORY ENDPOINTS ....................................................................................................... 80 
10.4.1 QUALITY OF LIFE (QOL)........................................................................................................... 80 
10.4.2 SECOND LINE TREATMENT ....................................................................................................... 80 
10.5 PHARMACOKINETICS ................................................................................................................. 80 
10.6 IMMUNE RESPONSE BIOMARKERS AND GENE EXPRESSIONS ................................................. 80 
10.7 SAMPLE SIZE CALCULATION .................................................................................................... 80 
11 ADMINISTRATIVE PROCEDURES ........................................................................................... 82 
11.1 REGULATORY AND ETHICAL COMPLIANCE ............................................................................. 82 
11.2 INSURANCE ................................................................................................................................. 82 
11.3 RESPONSIBILITIES OF THE INVESTIGATOR AND IRB/IEC ...................................................... 82 
11.4 INFORMED CONSENT ................................................................................................................. 82 
11.5 LEUKAPHERESIS PROCEDURE INFORMED CONSENT FORM ................................................... 83 
11.6 AMENDMENTS TO THE PROTOCOL ........................................................................................... 83 
11.7 DISCONTINUATION OF THE STUDY ........................................................................................... 83 
11.8 STUDY DRUG SUPPLY AND RE-SUPPLY, STORAGE AND TRACKING/DRUG ACCOUNTABILITY
 
83 

 
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12 PROTOCOL ADHERENCE .......................................................................................................... 85 
13 REFERENCES (AVAILABLE UPON REQUEST) ......................................................................... 86 
14 APPENDICES ................................................................................................................................ 88 
14.1 FACT-P QUESTIONNAIRE ......................................................................................................... 88 
14.2 EQ-5D QUESTIONNAIRE ............................................................................................................ 92 
14.3 NCI CTCAE ............................................................................................................................... 95 
14.4 PROTOCOL VIOLATIONS/DEVIATIONS ..................................................................................... 95 
 
 
 
 
 
 

 
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LIST OF FIGURES 
Figure 1: DCVAC/PCa Phase III study design ...................................................................................................... 36 
 
 
LIST OF TABLES 
Table 1: Visit Evaluation Schedule ....................................................................................................................... 52 
Table 2: ECOG performance status scale .............................................................................................................. 65 
 
 
 
 

 
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ABBREVIATIONS 
Abbreviation or Term* 
Definition/Explanation 
ACE 
angiotensin converting enzyme 
ACI 
active cellular immunotherapy 
ADR 
adverse drug reaction 
ADT 
androgen deprivation therapy 
AE 
adverse event 
AESI 
Adverse Events of Special Interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ANCA 
anti-neutrophil-cytoplasmic antibodies 
aPTT 
activated partial thromboplastin time 
ARS 
all randomized subjects 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Class  
ATMP 
advanced-therapies medicinal products 
Ca2+ 
Calcium ion 
CBC 
complete blood count 
CHMP 
Committee for Medicinal Products for Human Use 
CMV 
cytomegalovirus 
Cl- 
chloride ion 
CRF 
case report form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRPC 
castration-resistant prostate cancer 
CT 
computed tomography 
DC 
dendritic cell 
DCVAC/PCa 
Autologous active cellular immunotherapy consisting of 
dendritic cells for prostate cancer treatment 
DMSO 
Dimethyl sulfoxide 
DNA 
Deoxyribonucleic acid 
DQF 
Data Query Form 
DSUR 
Development Safety Update Report 

 
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EBV 
Epstein-Barr Virus 
EC/IEC 
Ethics Committee / Independent Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EC 
European Commission / European Community  
EDC 
Electronic Data Capture 
EMA/EMEA 
European Medicines Agency 
EOT 
End of Treatment 
EOS 
End of Study 
EORTC 
European Organization for the Research and Treatment 
of Cancer 
EQ-5D 
Euro Quality of Life 5 Dimensions 
EU 
European Union 
FACT-P 
Functional Assessment of Cancer Therapy - Prostate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage colony stimulating factor 
GMP 
Good Manufacturing Practice  
GMT 
gamma-glutamyltransferase 
GnRH/LHRH 
gonadotropin releasing hormone/ luteinizing hormone-
releasing hormone 
HBc Ab 
Hepatitis B Core Antibody 
HBs Ag 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HHP 
high hydrostatic pressure 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HPF 
high-power field 
HR 
heart rate 
HTLV 
IB 
human T-lymphotropic virus 
Investigator Brochure 
ICF 
Informed Consent Form 
iDCs 
immature dendritic cells 
IDMC 
Independent Data Monitoring Committee 

 
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IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
Investigational New Drug 
IRB 
Investigational Review Board 
IRF 
Independent Review Facility 
ITT 
Intent to treat 
IVRS/IWRS 
Interactive Voice Response System / Interactive Web 
Response System 
K 
Potassium 
Kg 
Kilogram 
LDH 
lactate dehydrogenase 
LNCaP 
androgen-sensitive prostate cancer cell line derived from 
lymph node metastasis  
LOCF 
last observation carried forward 
LVEF 
Left Ventricular Ejection Fraction 
NK cells 
Natural killer cells 
mCRPC 
Metastatic Castration Resistant Prostate Cancer 
mDCs 
mature dendritic cells 
MDSC 
myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
Mg 
Magnesium 
MHC 
major histocompatibility complex 
MR 
median reference 
MRI 
magnetic resonance imaging 
MS 
Median survival 
MT 
median test 
MUGA 
multiple gated acquisition 
Na 
Sodium 
NaCl 
sodium chloride 
NCCN/EAU 
National Comprehensive Cancer Network /European 
Association of Urology 

 
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NCI CTCAE 
National Cancer Institute - Common Terminology 
Criteria for Adverse Events  
NP 
nurse practitioner 
OS 
overall survival 
PA 
physician Assistant 
PBMC 
peripheral blood mononuclear cells 
PCa 
prostate cancer 
PCR 
polymerase chain reaction 
PCWG 
Prostate Cancer Working Group 
PE 
physical examination 
PD 
progressive disease 
rPFS 
radiographic progression free survival 
pH 
negative logarithm of hydrogen ion concentration 
(“power of hydrogen”) 
PP 
per protocol set of subjects 
PR 
partial response 
PSA 
prostate-specific antigen 
PSADT 
prostate-specific antigen doubling time 
PT 
prothrombin time 
QoL 
quality of life 
RBC 
red blood cell 
RECIST 
response evaluation criteria in solid tumors 
RF 
rheumatoid factors 
RNA 
ribonucleic acid 
RPE 
radical prostatectomy 
SAE 
serious adverse event 
SAP  
Statistical Analysis Plan 
SAR 
serious adverse reaction 
SD 
stable disease 
SIV 
site initiation visit 
SmPC 
Summary of Product Characteristics 
SOC 
Standard of Care 
SPECT 
single-photon emission computed tomography 
SRE 
skeletal related events 
SUKL 
State Institute for Drug Control (e.g. Czech Competent 
Authority in the Czech Republic) 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 

 
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TSH 
thyroid - stimulating hormone 
TTP 
time to progression 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
VHP 
Voluntary Harmonisation Procedure 
WBC 
white blood cell 
WHO 
World Health Organization 

 
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ONCOLOGY CLINICAL STUDY PROTOCOL SYNOPSIS  
Name of Sponsor / 
Company 
SOTIO a.s. 
Investigational drug  
DCVAC/PCa, active cellular immunotherapy containing autologous dendritic cells 
(DC) activated by transient exposure to killed prostate cancer cells ex-vivo 
Protocol no. 
SP005 
Study phase 
Phase III 
Study title 
A Randomized, Double Blind, Multicenter, Parallel-Group, Phase III Study to Evaluate 
Efficacy and Safety of DCVAC/PCa Versus Placebo in Men with Metastatic Castration 
Resistant Prostate Cancer Eligible for 1st Line Chemotherapy 
Background 
DCVAC/PCa is an active autologous cellular immunotherapy consisting of dendritic 
cells (DCs) produced ex-vivo from a patient’s monocytes which are pulsed with tumor 
cells killed by high hydrostatic pressure (HHP) and subsequently activated by a 
maturation agent. When the activated autologous DCs are injected back into the patient 
with mCRPC an immune response is established against the cancer which may inhibit 
progression and improve overall survival (OS). 
Purpose/rationale 
Addition of DCVAC/PCa to Standard of Care (SOC) Chemotherapy (docetaxel plus 
prednisone) will result in a prolongation in OS in mCRPC subjects. 
Objectives 
Primary: 
The primary objective is to show superiority of treatment with DCVAC/PCa in addition 
to SOC (docetaxel plus prednisone) over placebo in addition to SOC (docetaxel plus 
prednisone) in men with mCRPC as measured by OS. 
 
Key Secondary: 
The key secondary objectives include assessments of safety, treatment group 
comparison with regards to radiographic progression free survival, time to prostate-
specific antigen progression, time to first occurrence of skeletal related events (SRE). 
 
Other Secondary: 
Show clinical benefit of treatment with DCVAC/PCa in addition to SOC over placebo 
in addition to SOC with regard to time to radiographic progression or to skeletal related 
events and proportion of patients with SRE. 
 
Exploratory Objective: 
Treatment group comparison for the following measures: Proportion of subjects 
requiring second line treatment introduction and time to second line therapy, changes 
in quality of life (QoL) and exploratory studies for search of potential biomarkers 
Endpoints  
Primary efficacy endpoint:  
 
Overall Survival (OS) 
 
Key Secondary efficacy endpoints: 
 
Radiological progression free survival (rPFS), composite of 
o 
radiographic progression of bone lesions 
o 
radiographic progression of soft tissue lesions 
o 
death due to any cause 
 
Time to prostate-specific antigen (PSA) progression 
 
Time to first skeletal related events (SRE) 
 
 

 
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Other Secondary efficacy endpoints: 
 
Time to radiographic progression or SRE  
 
Proportion of patients with SRE 
 
Safety endpoints: 
Adverse events, including laboratory abnormalities, change in vital signs and change 
in ECOG performance status. 
 
Exploratory endpoints: 
 
Evaluation of QoL using the standardized questionnaires FACT-P and EQ-5D 
(EQ-5D only in Europe) 
 
Proportion of subjects requiring second line treatment introduction  
and time to second line therapy 
 
Exploratory studies for search of potential biomarkers 
Study design 
This is a randomized, double blind, placebo controlled, multicenter, international, 
parallel-group Phase III study to evaluate the efficacy and safety of DCVAC/PCa 
versus placebo in men with metastatic castration resistant prostate cancer (mCRPC) 
eligible for 1st line chemotherapy with docetaxel plus prednisone. The sample size was 
established as 1170 subjects, and final analysis is planned after 657 deaths have 
occurred. 
  
The study will consist of: 
 
Screening Period (up to 28 days). 
 
Randomization – Interactive Voice/Web Response System (IVRS/IWRS) central 
randomization – 2:1 randomization Standard of Care Chemotherapy (docetaxel 
plus prednisone) + DCVAC/PCa or Standard of Care chemotherapy (docetaxel 
plus prednisone) + placebo. 
 
Leukapheresis Period – all subjects will undergo a leukapheresis evaluation prior 
the leukapheresis procedure. The leukapheresis procedure itself will be performed 
within 14 days of randomization. 
 
Concurrent Treatment Period – First line Standard of Care chemotherapy with 
docetaxel plus prednisone will begin 3 to 7 days after the leukapheresis procedure. 
All subjects will receive treatment per the prescribing information for the 
Standard of Care chemotherapy (docetaxel plus prednisone). DCVAC/PCa or 
placebo will be administered concurrently every 3 weeks. DCVAC/PCa or 
placebo will be administered at least 7 days before or at least 7 days after the 
nearest chemotherapy (Day 8-15 of chemotherapy cycle) starting after second 
cycle of Standard of Care chemotherapy (docetaxel+prednisone). 
 
Maintenance Boosting Period – should first line Standard of Care chemotherapy 
(docetaxel plus prednisone) be completed or withdrawn for any reason, the patient 
will continue on DCVAC/PCa or placebo every 4 weeks until the completion of 
a total of 15 doses, refusal, intolerance or introduction of the 2nd line of antitumor 
therapy. After completion or withdrawal of DCVAC/PCa or placebo an End of 
Treatment Visit (EOT) will be performed. 
 
Follow-up Period – All subjects will be followed until refusal, death or study 
closure. Final Analysis will be performed upon reaching the targeted number of 
events for analysis (657 deaths). Upon completion of the follow-up period patients 
will have the End of Study visit performed.  
Population 
Men with mCRPC who are eligible to receive first line Standard of Care chemotherapy 
with docetaxel plus prednisone 
Inclusion/exclusion 
criteria 
Inclusion 
 Male 18 years and older.  
 Histologically or cytologically confirmed prostate adenocarcinoma. 

 
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 Presence of skeletal and/or soft-tissue/visceral/nodal metastases according to one 
of the following criteria:  
 
Confirmed pathological fracture related to the disease. 
OR 
 
Confirmation of distant bone and/or soft-tissue and/or visceral metastases 
through at least one imaging modality including CT or MRI or scintigraphy 
scan (confirmation by independent review facility (IRF) required) 
OR 
 
Positive pathology report of metastatic lesion. 
 Disease progression despite androgen deprivation therapy (ADT) as indicated by:  
 
PSA increase that is ≥ 25% and ≥ 2 ng/mL above the minimum PSA as 
reached during ADT or above the pre-treatment level, if no response was 
observed and which is confirmed by a second value 1 or more weeks later.  
OR 
 
Progression of measurable lymph nodes (short axis ≥ 15 mm) or visceral 
lesion measurable per RECIST v1.1 criteria (confirmation by IRF 
required); 
OR 
 
Two or more new lesions appearing on bone scan/imaging compared with 
a previous scan (confirmation by IRF required) 
 Maintenance of castrate condition: Subjects, who have not had a surgical 
orchiectomy, must continue with hormone therapy (GnRH/LHRH agonists or 
antagonists) to reach levels of serum testosterone of ≤ 1.7 nmol/L (50 ng/dL). The 
duration of the castration period must be at least 4 months before screening.  
 Laboratory criteria: 
 
White blood cells greater than 4,000/mm3 (4.0 x109/L). 
 
Neutrophil count greater than 1,500/mm3 (1.5 x109/L). 
 
Hemoglobin of at least 10 g/dL (100g/L). 
 
Platelet count of at least 100,000/mm3 (100 x109/L). 
 
Total 
bilirubin 
within 
normal 
limits 
(benign 
hereditary 
hyperbilirubinaemias, e.g. Gilbert´s syndrome are permitted).  
 
Serum alanine aminotransferase, aspartate aminotransferase, and creatinine 
<1.5 times the ULN.  
 Life expectancy of at least 6 months based on Investigator´s judgment. 
 Eastern Cooperative Oncology Group (ECOG) performance status 0-2.  
 At least 4 weeks after surgery or radiotherapy before randomization.  
 A minimum of 28 days beyond initiation of bisphosphonate or denosumab therapy 
before randomization. 
 Recovery from primary local surgical treatment, radiotherapy or orchiectomy 
before randomization. 
 Signed informed consent including patient’s ability to comprehend its contents. 
 
Exclusion 
 Confirmed brain and/or leptomeningeal metastases (other visceral metastases are 
acceptable). 
 Current symptomatic spinal cord compression requiring surgery or radiation 
therapy. 
 Prior chemotherapy for prostate cancer  
 Patient co-morbidities: 
 
Subjects who are not indicated for chemotherapy treatment with first line 
Standard of Care chemotherapy (docetaxel and prednisone). 
 
HIV positive, HTLV positive. 
 
Active hepatitis B (HBV), active hepatitis C (HCV), active syphilis.  

 
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 
Evidence of active bacterial, viral or fungal infection requiring systemic 
treatment. 
 
Clinically significant cardiovascular disease including:  
 
symptomatic congestive heart failure.  
 
unstable angina pectoris.  
 
serious cardiac arrhythmia requiring medication. 
 
uncontrolled hypertension. 
 
myocardial infarction or ventricular arrhythmia or stroke within a 6 
months before screening, known left ventricular ejection fraction 
(LVEF) < 40% or serious cardiac conduction system disorders, if a 
pacemaker is not present.  
 
Pleural and pericardial effusion of any CTCAE grade. 
 
Peripheral neuropathy having a CTCAE ≥ grade 2. 
 
History of active malignant disease (with the exception of non-melanoma 
skin tumors) in the preceding five years. 
 
Active autoimmune disease requiring treatment. 
 
History of severe forms of primary immune deficiencies. 
 
History or anaphylaxis or other serious reaction following vaccination. 
 
Known hypersensitivity to any constituent in of the DCVAC/PCa or 
placebo product 
 
Uncontrolled co-morbidities including, psychiatric or social conditions 
which, in the Investigator’s opinion, would prevent participation in the trial. 
 Systemic corticosteroids at doses greater than 40 mg hydrocortisone daily or 
equivalent for any reason other than treatment of prostate cancer (PCa) within 6 
months before randomization. 
 Ongoing systemic immunosuppressive therapy for any reason.  
 Treatment with anti-androgens, inhibitors of adrenal-produced androgens or other 
hormonal tumor-focused treatment performed on the day of randomization (except 
for GnRH/LHRH agonists or antagonists), to exclude possible anti-androgen 
withdrawal response. This criterion is not applicable to subjects who have never 
responded to anti-androgen treatment, as there is no risk of anti-androgen 
withdrawal response. 
 Treatment with immunotherapy against PCa within 6 months before randomization. 
 Treatment with radiopharmaceutical within 8 weeks before randomization. 
 Participation in a clinical trial using experimental therapy within 4 weeks before 
randomization. 
 Participation in a clinical trial using immunological experimental therapy (e.g., 
monoclonal antibodies, cytokines or active cellular immunotherapies) within 6 
months before randomization. 
 Refusal to sign the informed consent.  
Patient numbering 
Subjects will be centrally randomized and assigned a unique study number using an 
IVRS/IWRS system. 
Investigational and 
Standard of Care drugs 
Investigational therapy:  
DCVAC/PCa is an active autologous cellular immunotherapy produced under GMP-
conditions. DCVAC/PCa is prepared on an individual basis from the peripheral blood 
mononuclear cells (PBMC) of the patient obtained by leukapheresis. DCs are generated 
from the harvested PBMCs using IL-4 and GM-CSF. Subsequently, the immature DCs 
(iDCs) are exposed to killed tumor cells (LNCaP) at a DC: tumor cell ratio of 5:1. 
Tumor cell-pulsed DCs are then matured by TLR-3 ligand. Cells are then 
cryopreserved and stored in liquid nitrogen. On the day of drug injection, a suspension 
of 1×107 LNCaP-pulsed mature DCs is unfrozen, re-suspended in 0.9% saline to a total 
volume of 5 ml and then injected subcutaneously in the inguinal and axillary lymph 
node area in two 2.5 mL volumes. The placebo used for the study will be identical to 
the study drug without the active drug substance (DCVAC/PCa). 

 
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Medication labels will comply with the legal requirements of each country and will be 
printed. Labels will contain the unique identification number of the patient and the 
LOT number. The storage conditions for study drug will be described on the secondary 
package label. 
 
Standard of Care therapies: Investigators should use Standard of Care therapy 
(docetaxel plus prednisone) with authorization for their country and should reference 
the prescribing information provided with the product when treating the subjects. 
Dose, regimen, 
treatment cycle 
Subjects receiving DCVAC/PCa or placebo will all receive prepared study medication 
according to the treatment plan. Concurrently with Standard of Care (docetaxel plus 
prednisone) DCVAC/PCa or placebo will be given in 3 weeks intervals (with an 
acceptable window of ± 7 days). DCVAC/PCa or placebo will be administered at least 
7 days before or and at least 7 days after the nearest chemotherapy (Day 8-15 of 
chemotherapy cycle). 
After discontinuation of Standard of Care chemotherapy for any reason, each following 
dose of DCVAC/PCa or placebo will be given in 4 weeks intervals (with an acceptable 
window of -7/+14 days) for up to a total of 15 doses.  
 
All subjects will receive first line Standard of Care chemotherapy (docetaxel plus 
prednisone) until completion, refusal, intolerance, disease progression or death and 
may be treated with subsequent therapies at the Investigator’s discretion (see section 
6.1.2) until completion, refusal, death or study closure. When 2nd line therapy is 
introduced to patient, DCVAC/PCa will be discontinued.  
Supply, preparation, 
and administration 
DCVAC/PCa is an autologous cellular suspension, 15 doses are manufactured from an 
autologous sample, 1 mL i.e. 1×107 pulsed mature DCs per dose, every dose diluted 
with 0.9% saline to a final volume of 5 mL. Each dose is given in 2 separate 2.5 mL 
subcutaneous injections, one injection to an inguinal lymph node area and one to an 
axillary lymph node area. Treatments are rotated to alternate areas. 
Visit schedule and 
assessments 
 
Laboratory evaluations during the Concurrent Treatment Period, while patient is 
on first line chemotherapy: 
 
Hematology every 3 weeks. 
 
Blood biochemistry every 3 weeks (includes ALP and LDH). 
 
TSH every 12 weeks 
 
PSA every 12 weeks (coordinated with imaging assessments). 
 
Urinalysis every 6 weeks. 
 
Laboratory evaluations during the Maintenance Boosting Period, after termination 
of first line chemotherapy:  
 
Hematology every 4 weeks until End of Treatment Visit. 
 
Blood biochemistry every 4 weeks (includes ALP and LDH) until End of 
Treatment Visit. 
 
TSH every 12 weeks until End of Treatment Visit. 
 
PSA every 12 weeks (coordinated with imaging assessments) until confirmed 
progression or introduction of 2nd line therapy. 
 
Urinalysis every 12 weeks until visit End of Treatment visit   
 
Blood sampling for research purposes – at Randomization, prior to the 5th dose of 
DCVAC/PCa or placebo, at the End of Treatment visit. 
 
Serum testosterone level at screening if historically measured value (older than 4 
months before screening) doesn´t exist. 
 
Complete Physical exam at screening. 
 
Symptom Directed Physical exam, vital signs every visit post screening. 
 
Imaging will be conducted every 12 weeks (± 7 days) (skeletal scintigraphy/CT 
(MRI)) until confirmed progression or until introduction of 2nd line therapy. 

 
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Special safety 
assessment(s) 
Safety assessments consist of monitoring and recording of all AEs, including serious 
adverse events (SAEs), the regular monitoring of hematology, blood biochemistry and 
urine values, clinical evaluation of vital signs, physical examinations, performance 
status using ECOG scale, and radiological examinations.  
An independent Data Monitoring Committee (IDMC) will be constituted to regularly 
evaluate blinded safety data. 
Patient reported 
outcomes 
QoL based on the questionnaires FACT-P and EQ-5D (EQ-5D only in Europe). 
Biomarkers 
PSA measured as part of secondary endpoint of disease progression. 
Exploratory Biomarker 
Immunogenicity 
studies 
Blood samples for research purposes will be obtained from all subjects at 
Randomization, at cycle 5 week 2, and at the End of Treatment visit. Serum and cells 
will be frozen for biomarker research evaluation. 
Independent DMC 
The IDMC will meet regularly per the charter to review accruing safety data. It is 
expected that the IDMC will consist of five members, including one statistician. The 
frequency of IDMC meetings will be spelled out in the IDMC charter. 
Statistical methods and 
data analysis 
It is planned that the data from all centers that participate in this protocol will be used, 
so that an adequate number of subjects will be available for analysis (ITT population). 
 
Data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, and safety observations and measurements. 
 
The assessment of efficacy will be based on a sample size of approximately 1170 
subjects (i.e., events of 657 deaths). The study will have 80% power to detect a hazard 
ratio of 0.792 for death in the group receiving DCVA/PCa plus Standard of Care 
chemotherapy (docetaxel plus prednisone) as compared with the group receiving 
placebo plus Standard of Care Chemotherapy (docetaxel plus prednisone). This sample 
size was calculated by assuming a median survival of 24 months for the DCVAC/PCa 
group and 19 months for the control group, with a two-sided significance level (alpha) 
of 0.05, allocation ratio 2:1 of DCVA/PCa versus placebo arm, an enrollment period 
of approximately 18 months, and total study duration of approximately 40 months to 
observe the required event-driven timeframe of 657 total events for the final analysis. 
If the anticipated 657 events are not attained during the trial timeline, the study could 
be extended by SOTIO.  
 
The primary efficacy analysis is a stratified log-rank test of the overall survival (OS) 
endpoint to compare subjects receiving DCVAC/PCa in addition to Standard of Care 
(docetaxel plus prednisone) (Arm A) versus those receiving placebo in addition to 
Standard of Care (docetaxel plus prednisone) (Arm B) for the Intent-to-Treat (ITT) 
population. Patients will be randomized in a 2:1 ratio, stratified by region (US vs 
Other), prior therapy (abiraterone or enzalutamide or neither of the two) and, ECOG 
Score (0, 1 vs 2). The overall type I error rate will be controlled at 0.05. At the final 
analysis, a final p-value of ≤ 0.0455 is required to be considered statistically significant. 
(East 5.4 software with ‘Null’ variance was used for total events and statistical 
significance boundary determination). 
The Cox proportional hazards regression model will be used to analyze OS data. 
Estimated hazard ratio and corresponding two-sided 95% confidence interval will be 
calculated. Estimated median survival time and survival rate will be calculated and 
presented by treatment group.  
 
The assessment of safety will be based mainly on the comparison of frequency of AEs 
and related AEs (ADRs) between groups. Adverse events will include clinically 
significant laboratory abnormalities.  
 
Patient reported outcomes will be assessed using the questionnaires FACT-P and EQ-
5D (EQ-5D only in Europe). 

 
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Number of subjects, 
centers and location, 
predicted duration 
Total number of subjects: 
Number of sites: 
Number of subjects per site: 
Location of sites: 
Predicted duration: 
1170 subjects 
280 – 320 centers 
 4 – 12 per site 
Europe, the USA and Canada 
40 months 
 

 
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1 
BACKGROUND 
 
1.1 
Overview of Prostate Cancer 
Prostate cancer (PCa) is the second most common form of cancer and the sixth leading cause 
of cancer death among men worldwide with an estimated 899,000 new cases and 258,000 new 
deaths in 2008.1 The worldwide PCa burden is expected to grow to 1.7 million new cases and 
499,000 new deaths by 2030 simply due to the growth and aging of the global population.1 The 
incidence of prostate cancer varies greatly in individual geographic regions and countries of the 
world. The highest incidence in 2008 was estimated to be in France (Martinique 173.3/100,000) 
and in Northern Europe (Ireland 126.3/100,000, Norway 115.6/100,000, and Sweden 
114.2/100,000). In Australia and New Zealand the estimated incidence in 2008 was 
104.2/100,000. In Central and Eastern Europe the average incidence of prostate cancer in 2008 
was estimated to be 28.5/100,000 (57,554 cases), in Northern Europe 75.2/100,000 (67,638 
cases), in Southern Europe 50.2/100,000 (79,923 cases) and in Western Europe 94.1/100,000 
(170,007 cases). In the USA, prostate cancer accounted for an estimated 186,220 new cases in 
2008 (incidence 83.8/100,000 men).2 It is estimated that 240,890 men were diagnosed with the 
disease and 33,730 died of it in the USA in 2011.3 An estimated 238,590 new cases of prostate 
cancer will occur in the US during 2013 with an estimated 29,720 deaths in 2013, prostate 
cancer is the second-leading cause of cancer death in men in the US.4 
 
Well-established risk factors for PCa are older age, black race/ethnicity, and a family history of 
the disease.5 Race is a prostate cancer risk factor and a cancer prognostic factor. Currently, 
African-American or black men have a risk of diagnosis that is 1.6 times above the risk in white 
men and risk of death that is 2.5 times greater.6 
 
Prostate cancer treatment options include surgery (prostatectomy), radiotherapy, hormonal 
manipulation and chemotherapy.7,8 Prostate cancer can be cured at the stage of localized organ-
confined disease, in which 10-year survival is between 75 and 93%.9 In spite of good results of 
radical prostatectomy (RPE) or primary curative radiotherapy, relapses occur in approximately 
30% of subjects within 5 years after primary curative treatment. Relapse risk factors include 
Gleason score and PSA value at diagnosis.  
 
Subjects with locally advanced or metastatic carcinoma have significantly poorer prognosis. 
Treatment of locally advanced disease consists of a combination of surgery or radiotherapy and 
androgen deprivation therapy (ADT). Subjects with metastatic disease are candidates for ADT 
by orchiectomy or pharmacological agents. ADT leads to apoptosis of primary tumor cells as 
well as metastases. ADT reduces symptoms and delays the time to progression (TTP), however, 
it does not prolong the OS.  
 
Average responsiveness to castration for men with metastases varies between 18 and 48 months. 
Frequently, despite ADT, disease progression occurs, due to the emergence of resistant tumor 
cells and castration-resistant disease develops. Median survival of metastatic castration-
resistant subjects varies between 12–36 months depending on the risk factors. Palliative 
targeting of bone metastases with bisphosphonates, RANK ligand inhibitors, or beta-emitting 
radiopharmaceuticals improves quality of life but has no effect on the overall survival. Several 

 
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therapies have now been approved by the Food and Drug Administration (FDA) agency, for the 
treatment of castration resistant prostate cancer (CRPC) including chemotherapy (docetaxel and 
cabazitaxel), 
secondary 
hormonal 
manipulation 
(abiraterone, 
enzalutamide), 
radiopharmaceutical Radium-223 dichloride to treat bone metastases and cell-based 
immunotherapy (sipuleucel-T). Each of these prolongs median survival by a few months. As a 
result, there is a clear unmet medical need for an agent that can provide clinically relevant 
improvement in the OS or/and progression free survival (PFS) without adding to the existing 
burden of intolerability. DCVAC/PCa is being considered as an additional option for the 
mCRPC subjects requiring Standard of Care 1st line chemotherapy, to prolong OS. 
 
1.2 
Immunotherapy in Prostate Cancer 
In light of the recent advances in understanding the biology of the immune response and the 
importance of an anti-tumor immune response for long-term prognosis of cancer, 
immunotherapy has emerged as another treatment modality with the potential to contribute to 
further improvements in survival.10 Recently, the FDA approved the first cell-based 
immunotherapy (sipuleucel-T; April 29, 2010; BL 125197/0; License No. 1749) as the first 
application of this new approach in clinical practice. 
 
Immunotherapy is based on the induction of tumor cell specific immune response that 
subsequently recognizes and destroys tumor cells. Cell-based immunotherapy must stimulate 
specific immune responses against cancer cells, and the immune responses must be sufficient 
to overcome the immuno-suppressive mechanisms of tumor tissue micro-environment.11 These 
mechanisms represent the main obstacle limiting the efficacy of immunotherapy in advanced 
stages of cancer if applied as monotherapy. Thus, the combination of chemotherapy drugs with 
immunotherapy seems to be a rational approach in CRPC subjects. Chemotherapy, which is 
broadly viewed as immuno-suppressive, might to some extent boost an anti-tumor response.12,13 
Indeed, studies have shown that chemotherapy can be combined with a cell-based 
immunotherapy for prostate-cancer without blunting the immune response to the 
immunotherapy.13 A summary of immunotherapy of prostate cancer is provided in the 
Investigator’s Brochure (IB). 
 
The approach tested in this study represents a patient specific active cellular immunotherapy 
(ACI) using autologous dendritic cells differentiated from peripheral blood monocytes and 
presenting tumor antigens derived from prostate cancer cell line killed by an immunogenic cell 
death. In the present study, ACI will be combined with the first line chemotherapy (docetaxel 
plus prednisone) in accordance with the concept of “chemo-immunotherapy”. 
 
1.3 
Overview of DCVAC/PCa  
DCVAC/PCa is an autologous active cellular immunotherapy which was previously considered 
to be a medical treatment, not requiring drug-status authorization. In 2007 the European Union 
(EU) legislation classified this cellular therapy as a drug belonging to the category of advanced-
therapies medicinal products (ATMP) according to EC 1394/2007. In the USA, Human Cells, 
Tissues, and Cellular and Tissue Based Products are under regulation 21 CFR part 1271 issued 
in 2001. From October 2011 active cellular immunotherapy for cancer treatment is guided by 
Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines. 

 
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In compliance with these regulations and guidelines, DCVAC/PCa is produced under Good 
Manufacturing Procedure (GMP) conditions. DCVAC/PCa is prepared individually from the 
patient’s autologous peripheral blood mononuclear cells (PBMCs) obtained by leukapheresis. 
Immature DCs (iDCs) are differentiated from peripheral blood monocytes in the presence of 
IL-4 and GM-CSF. Subsequently the iDCs are exposed to a human prostate adenocarcinoma 
cell line (LNCaP) killed by an immunogenic cell death at a DC: tumor cell ratio of 5:1. LNCaP-
pulsed DCs are then matured by TLR-3 ligand (Poly I:C), incubated for 12 to 20 hours at 
37oC/5% CO2. Cells are then cryopreserved in CryoStor CS10 freeze medium at a concentration 
of 1x107/mL and stored in liquid nitrogen. These cells are stable for at least 18 months and 
aliquots can be stored at a drug depot and distributed to the clinical sites. On the day of drug 
administration, an aliquot of 1×107 LNCaP-pulsed mature DCs is thawed, re-suspended in 0.9% 
saline to a volume of 5 mL, and divided into two 2.5 mL injections for the patient’s comfort. 
The dose is then injected subcutaneously in the inguinal or and axillary regions within 30 
minutes after re-suspension. 
 
1.3.1 
Pre-clinical development 
Extensive in-vitro studies have been conducted to characterize the potency of DCVAC/PCa and 
to determine the biological activity of this cell-based immunotherapy. The guidelines on human 
cell-based medicinal products (EMEA/CHMP/410869/2006) state that in-vitro studies may 
replace animal studies if relevant animal models have not been developed. As animal models 
are not relevant for this kind of product due to its autologous nature, the pharmacokinetic 
properties and safety of the product were evaluated in human pilot studies. 
 
The capacity to activate antigen specific cytotoxic lymphocytes is a hallmark of mature DCs. 
The capacity of mature DCs to induce antigen specific T cells is tested in the potency assay. In 
this test, mature DCs are pulsed with the mixture of HLA class I binding peptides from influenza 
virus, CMV and EBV and tested for their capacity to expand virus specific T cells. As 
documented in internal validation study “Potential of mature dendritic cells as with regards to 
activation of specific cytotoxic T-lymphocytes” (VAL-54), mature DCs present in the 
DCVAC/PCa efficiently expand virus specific T cells after one week of co-culture with 
autologous T lymphocytes.  
 
The ability to induce tumor-specific cytotoxic CD8+ T lymphocytes can also be tested using 
mature DCs pulsed with killed tumor cells. DCs possess the capacity to present exogenous 
antigens (such as apoptotic tumor cells) at MHC class I molecules and thus can activate both 
CD4 and CD8 tumor cells specific T lymphocytes. DCVAC/PCa activates both CD4 and CD8 
LNCaP specific T lymphocytes after two weeks of culture.14 
 
1.3.2 
Clinical development 
 
Phase I/II  
The first-in-human study with DCVAC/PCa was initiated in 2008 (after GMP approval of 
manufacturing process by Czech national regulatory authority: SUKL - certificate for 
manufacturer No 21442/2/INS/07) in University Hospital Motol, Prague, Czech Republic. After 
local ethical committee approval, DCVAC/PCa was administered to the initial first patient, a 

 
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69 year old man with CRPC who failed docetaxel treatment.15 An additional nine CRPC 
subjects (60-83 years, median 69 years) have been treated with DCVAC/PCa after the first line 
chemotherapy failure, concomitantly with the first line chemotherapy or cell-based 
immunotherapy alone if chemotherapy was contraindicated. The median survival of these 
subjects with very advanced CRPC was longer than the survival estimated by the Halabi 
nomogram16 (for details, see IB). Up to 25 doses of DCVAC/PCa were administered in 5-7 
weeks intervals and no serious adverse reactions (SARs) have been reported.  
 
The investigator-driven academic study registered as EudraCT 2009-017295-24 was initiated 
in July 2010. In this on-going study, 17 subjects - median age 68 years (58-78 years), have been 
treated by with chemo-immunotherapy. DCVAC/PCa is administered in combination with 
docetaxel at the standard dose of 75 mg/m2 every 3 weeks and prednisone 5 mg twice daily. 
The primary endpoint of this study was safety, secondary endpoint was OS and the presence of 
tumor specific immune response.  
 
As part of this study, a bio-distribution study was performed using DCVAC/PCa labeled with 
indium (111In)-oxine. Labeled DCVAC/PCa in the final volume of 1 mL (6 MBq/mL) was 
administered subcutaneously into the bilateral axillary and inguinal areas. Nuclear scintigraphy 
and SPECT fused with low-dose CT images were used to visualize the migration of 
DCVAC/PCa to the lymph nodes. The effectiveness of labeling was 81%. Scintigraphic images 
of these areas were carried out for at 1, 4, 24, and 48 hours. Over the period of 48 hours, fused 
SPECT/low-dose CT scans were performed targeting the application site. Imaging methods 
showed that after DCVAC administration, labeled DCs migrated into the regional lymph nodes 
(see IB). 
 
In 2010, another investigator-driven academic phase I/II single-center open-label study was 
initiated in prostate cancer subjects with rising PSA within 2 years after primary prostatectomy 
or at any time after salvage radiotherapy (EudraCT: 2009-017259-91). The primary end-point 
is safety and toxicity, secondary end-points are PSA response and immunological response.  
 
The number of subjects enrolled in this study was extended from 15 to 25 by a protocol 
amendment in 2011. In this study, DCVAC/PCa is administered every 4 weeks as a 
monotherapy for the period of one year. Metronomic cyclophosphamide 50 mg daily for one 
week is administered prior to the initiation of the active cancer immunotherapy. In a protocol 
amendment, extension of the administration period has been approved in those subjects who 
experienced prolongation of the PSADT on immunotherapy in comparison with the pre-
treatment period. This study is still ongoing, 24 subjects were enrolled in the study. Median age 
of this group of enrolled subjects is 63 years (51-74 years). Preliminary data show the 
prolongation of PSADT in the majority of subjects during immunotherapy in comparison with 
the pre-treatment period (see IB).  
 
Safety  
All subjects are followed for possible induction of auto-immunity at one month intervals. 
Evaluated parameters include: serum antibody concentrations (IgG, IgA, IgM, IgE), 

 
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complement C3 and C4 concentrations, detection of monoclonal M component, antinuclear 
antibodies (ANA), anti-neutrophil – cytoplasmic antibodies (ANCA), anti-Fc Ig antibodies 
(rheumatoid factors in IgG, A and M isotypes – RF IgG, RF IgA and RF IgM), anti-
transglutaminase antibodies, CRP. So far, there have been no significant laboratory changes in 
screened parameters before, during or after the study treatment. One patient had detectable RF 
IgM without clinical signs of rheumatic disease before immunotherapy and the level did not 
fluctuate during the treatment period.  
 
As of March 2013, 738 doses of DCVAC ACI have been administered to the 50 subjects in the 
phase I/II studies; 40 subjects in the framework of the two clinical trials (EudraCT 2009-
017259-91 and 2009-017295-24) and 10 subjects on an individual basis outside the scope of 
the clinical trials starting in 2008. 
 
Out of 45 reported SAEs within the phase I/II clinical studies with DCVAC/PCa including 
subjects treated on individual basis (cumulative number from DSUR #1 and DSUR #2), none 
were assessed as a DCVAC/PCa-related SAE and the majority of them were associated with 
the progression of underlying disease. During the current reporting period, the ongoing clinical 
program with DCVAC/PCa has not raise any new safety concerns associated with the 
investigated immunotherapy. The most commonly reported AEs encompassed fatigue, 
gastrointestinal conditions, infections including renal and urinary disorders, and 
musculoskeletal pain. Autoimmunity examinations performed has not indicated any higher risk 
of autoimmunity in the subjects receiving DCVAC/PCa. No suspected unexpected serious 
adverse reaction (SUSAR) was reported by the investigator or Sponsor. No adverse events were 
recorded linked to the leukapheretic procedure. The first dose was administered to hospitalized 
subjects and vital signs were monitored. All other applications were administered in out-patient 
departments with 1 hour of observation. As no acute SAR related to study drug application 
administration has occurred so far, for future studies, out-patient department DCVAC/PCa 
administration is recommendable. 
 
Phase II 
A low production capacity in the University Hospital Motol GMP laboratory (2-3 individual 
DCVAC/PCa per month) and limited financial academic resources did not allow for further 
extension of clinical trials to fulfill all requirements necessary for the registration of this 
individual product. The biopharmaceutical company SOTIO a.s. assumed the responsibility for 
the further clinical development of DCVAC/PCa. The SOTIO a.s. production facility (with 
capacity for up to 60 individual DCVAC/PCa productions monthly) was opened in spring 2011 
and received GMP status in autumn 2011.  
 
SOTIO has conducted regulatory meetings with the European Medicinal Agency (EMA) and 
Food and Drug Administration (FDA) to discuss the manufacturing and clinical development 
plan of DCVAC/PCa.  
 October 
2010, 
EMA 
scientific 
advice 
for 
manufacturing 
processes 
EMEA/CHMP/SAWP/261301/2011.  

 
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 December 2011 SOTIO a.s. received a certificate of GMP compliance as a manufacturer 
from Czech Regulatory Authority (State institute for drug control – SUKL) Ref. No. 
sukls127848/2011 which fulfills EMA requirements.  
 January 2012, EMA scientific advice on preclinical and clinical development plan 
EMEA/CHMP/SAWP/99235/2012 and EMEA/CHMP/SAWP/99234/2012.  
 March 2012, SOTIO a.s. had a pre-IND face-to-face meeting with FDA.  
  
Based on the outcomes from the meeting with the EMA in 2010, four phase II trials were 
designed in 2011. These were approved by the Czech State Institute for Drug Control (SUKL) 
in December 2011 and initiated in March 2012: 
  
Clinical Trial SP001 (Eudra CT: 2011-004735-32): randomized, open-label, parallel-group, 
multi-center phase II clinical trial of active cellular immunotherapy with product DCVAC/PCa 
in patients with castrate-resistant prostate cancer. (In combination with docetaxel) 
 
Clinical Trial SP002 (Eudra CT: 2011-004986-34): randomized, open-label, parallel-group, 
multi-center phase II clinical trial of active cellular immunotherapy with product DCVAC/PCa 
in combination with hormone therapy in patients with metastatic prostate cancer. 
 
Clinical Trial SP003 (Eudra CT: 2011-004985-14): randomized, open-label, parallel-group, 
multi-center phase II clinical trial of active cellular immunotherapy with product DCVAC/PCa 
in patients with localized prostate cancer after primary radical prostatectomy. 
 
Clinical Trial SP004 (Eudra CT: 2011-004967-65): randomized, open-label, parallel-group, 
multi-center phase II clinical trial of active cellular immunotherapy with product DCVAC/PCa 
in patients with localized high-risk prostate cancer after primary radiotherapy.  
 
As of February 2013, there were 233 subjects enrolled/screened in total in the four phase II 
trials, 183 of them being randomized by May 6, 2013. 79 of these had the immune therapy 
treatment started.  
 
A DSUR covering the period 28-December 2011 through 27-December-2012, was submitted 
in February 2013. There were 16 SAEs reported in 8 subjects from clinical trials during the 
reporting period covered by this DSUR. Only two SAE subjects out of those 8 were exposed to 
DCVAC/PCa at the time of the event. None of the reported SAEs were related to the study drug 
DCVAC/PCa. No SUSAR has been reported in that period. 
 
Phase III 
SOTIO is trying to find the most effective way to a complete global clinical development 
process. Based on discussions with the FDA and the EMA, the proposed phase III clinical trial 
targets USA and European subjects with mCRPC, who are eligible for the initiation of docetaxel 
treatment. Enrolled subjects will receive DCVAC/PCa or placebo in combination with 
docetaxel plus prednisone. We believe that the mCRPC population selection will serve to 
demonstrate clinical efficacy while maintaining clinical trial feasibility. Targeting earlier stages 
of the disease might translate into better efficacy, however, the cost and duration of the clinical 

 
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trial would be prohibitive. The lack of reliable endpoint acceptance by the regulatory authorities 
also complicates clinical testing in subjects at earlier stages of the disease. The mCRPC patient 
population is selected based on the fact that the OS is the most acceptable endpoint from a 
regulatory point of view. The current protocol for phase III reflects these assumptions. 
 
1.4 
Overview of Standard of Care Therapies in mCRPC 
Based on improved survival benefits from two studies, docetaxel 75mg/m2 and prednisone 5 
mg bid every 3 weeks was approved by the FDA in 2004 and has become the “standard of care” 
first-line chemotherapy for CRPC.17,18 The first study of one thousand and six subjects, TAX 
327, showed an OS rate significantly higher (P=0.009) in the group treated every 3 weeks with 
docetaxel compared to treatment with mitoxantrone. The median duration of survival was 18.9 
months in the group given docetaxel compared to 16.5 months in the mitoxantrone group 
(P=0.002). The second study compared the combination of docetaxel/estramustine to 
mitoxantrone/prednisone in 684 subjects. The median duration of survival was significantly 
improved with docetaxel/estramustine over mitoxantrone/prednisone (17.5 vs. 15.6 months, 
respectively, (p=0.01) and superior median TTP was also detected (6.3 vs 3.2 months, 
respectively, p=0.001) in subjects treated with docetaxel/estramustine.  
 
Four drugs were approved for the treatment of mCRPC subjects after docetaxel failure (post-
docetaxel  
 Cabazitaxel in combination with prednisone is indicated for the treatment of subjects with 
mCRPC previously treated with a docetaxel based regimen.  
 Abiraterone is indicated with prednisone or prednisolone for the treatment of mCRPC in 
adult men whose disease has progressed on or after a docetaxel-based chemotherapy 
regimen.  
 Enzalutamide was approved for adult mCRPC subjects with metastatic castration-resistant 
prostate cancer who have progressed on or after docetaxel therapy. Enzalutamide doesn't 
require concomitant steroids. 
 
Radium-223, an alpha particle-emitting radioactive therapeutic agent was approved for the 
treatment of subjects with castration-resistant prostate cancer, symptomatic bone 
metastases and no known visceral metastatic disease. 
 
Abiraterone has also been recently approved in a pre-docetaxel setting. This protocol allows for 
use of abiraterone in the pre-docetaxel setting in line with the approved indication. Prior 
treatment with abiraterone (or enzalutamide) represents one of the stratification criteria at 
randomization to ensure similar proportion of abiraterone pre-treated subjects within 
DCVAC/PCa and placebo treatment arms.  
 
1.5 
History of Amendments 
 
SP005 Protocol version 
(date) 
Prepared for 
submission 
Key points for creation of an updated protocol version 
 (not all changes are listed in this overview)  
v.1.1 (07Mar2013) 
VHP No. 201302 
(positive decision 
19Mar2013) 
For version 1.1 positive decision was received in VHP 
submission.  

 
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SP005 Protocol version 
(date) 
Prepared for 
submission 
Key points for creation of an updated protocol version 
 (not all changes are listed in this overview)  
v.02 (10May2013) 
IND No. 015255 
(initial submission 
28May2013) 
Version 02 was based on v.1.1 and was modified for IND 
submission to FDA in USA. (Key changes included – 
specification of 1st line chemotherapy as docetaxel and 
prednisone and update of DCVAC/PCa safety information 
based on DSUR issued in February 2013; specification of 
exploratory studies on biomarkers; updated list of 
approved 2nd line chemotherapies).  
v.03 (01Aug2013) 
IND No. 015255 
(Follow up 
submission 
09Aug2013) 
Version 03 was based on v.02 and was modified per 
feedback received from FDA. (Key changes included –
Discontinuation of DCVAC/PCa or placebo with 2nd line 
chemotherapy; Treatment period divided into 2 periods - 
concurrent treatment of 1st line chemotherapy with 
DCVAC/PCa or placebo and Maintenance Boosting 
period post docetaxel-prednisone & prior 2nd line-
chemotherapy; changes connected with this design 
change; updated list of approved 2nd line chemotherapies; 
Amendment of stratification criteria, updated statistical 
section] 
v.04 (05Dec2013) 
VHP No.201302 
Substantial 
Amendment / IND 
No. 015255 Follow 
up submission  
Version 04 is based on v.03 and mostly operational details 
have been adjusted to match properly the new design in 
v.03 (Study drug discontinuation, End of Treatment, 
Follow-up for survival); secondary endpoints were 
modified to better fulfill PCWG2 recommendations; 
inclusion and exclusion criteria were modified per 
PCWG2 guidelines; corrected statistical section and 
decreased number of stratification criteria)  
v.05 (16Oct2014) 
VHP Substantial 
Amendment No.2 /  
IND No. 015255 
Follow up 
submission 
Version 05 includes updates based on current experience 
from the clinical trial - clarified inclusion/exclusion 
criteria; updated sections on patient follow-up for long 
term survival; sections related to safety were updated to 
improve understanding. Sections on interim analysis and 
statistical analyses were updated based on feedback 
received from FDA. Section on exploratory studies was 
updated to include possibility of pharmacogenomics 
research.  
v.05.1 (13Jan2015) 
IND No. 015255 
(Follow up 
submission) 
US specific protocol 
Change in the exclusion criterion. It is possible to shorten 
the washout period for ADT.  
v. 05.2 (03Aug2015) 
IND No. 015255 
(Follow up 
submission) 
US specific protocol 
Version 05.2 introduces: clarification of follow-up 
procedures applicable to patients for whom leukapheresis 
or production failed, or who have not received 
DCVAC/PCa or placebo for other reasons; clarification 
that no further radiological examinations of a patient will 
be required for this trial after confirmation of radiological 
progression or introduction of 2nd line chemotherapy; 
changes related to transfer of pharmacovigilance 
responsibilities for safety monitoring and reporting from 
Chiltern to SOTIO; administrative changes in the 
Declaration of the Investigator  

 
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SP005 Protocol version 
(date) 
Prepared for 
submission 
Key points for creation of an updated protocol version 
 (not all changes are listed in this overview)  
v. 06.0 (28Aug2015) 
VHP Substantial 
Amendment No.04 
Version 06.0 includes the same changes as US-specific 
versions 05.1 and 05.2 : change in wording of the 
exclusion criterion that shortens the ADT washout period; 
clarification of follow-up procedures applicable to 
patients for whom leukapheresis or production failed, or 
who have not received DCVAC/PCa or placebo for other 
reasons; clarification that no further radiological 
examinations of a patient will be required for this trial 
after confirmation of radiological progression or 
introduction of 2nd line chemotherapy; changes related to 
transfer of pharmacovigilance responsibilities for safety 
monitoring and reporting from Chiltern to SOTIO; 
administrative changes in the Declaration of the 
Investigator; Version 06.0 additionally includes the 
introduction of the EQ-5D questionnaire (only in Europe) 
and clarification that ECOG performance status is 
measured also at Randomization. 
v. 07.0 (08Mar2018) 
VHP Substantial 
Amendment 
No.08/IND No. 
015255 (Follow up 
submission) 
 
 Deletion of information on third-party vendors 
 Deletion of information on interim analysis which will 
not be performed 
 Clarification that the date of randomization is Day 1 
and not Day 0 
 Update of the sections on statistics according to the 
updated SAP 
 Clarification that ECOG performance status is 
measured also at Randomization  (already in 
European v. 06.0) 
 Introduction of the EQ-5D questionnaire (only in 
Europe) (already in European v. 06.0) 
 Safety reporting clarifications 
 
 

 
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2 
STUDY RATIONALE/PURPOSE 
For prostate cancer subjects with metastatic disease, androgen ablation with surgery or drugs 
remains the standard of care. The majority of subjects initially respond, but despite androgen 
ablation, all eventually progress and become castration resistant after a median duration of 
approximately 18-48 months. Docetaxel is currently the only primary first-line chemotherapy 
option in subjects who have developed symptomatic or rapidly progressive hormone 
refractory/castration resistant metastatic PCa with a survival advantage of about 3 months.7,8 
 
Single agent autologous immunotherapy has demonstrated survival benefit in CRPC in subjects 
who are asymptomatic or minimally symptomatic or non-symptomatic.19 Combination therapy 
with autologous immunotherapy and standard of care chemotherapy may prove to have even 
greater survival benefit to subjects.  
 
2.1 
Rationale for Chemo-immunotherapy 
The goal of immunotherapy in advanced cancer subjects is not the complete eradication of 
tumor cells but rather a reversal from the escape phase back to the equilibrium stage.12 Therefore 
appropriate combination of tumor mass reduction and neutralization of tumor-induced immuno-
suppression might set the right conditions for the induction of anti-tumor immune response by 
the active immunotherapy of choice.  
 
In contrast to the prevailing view of chemotherapy as an immuno-suppressive regimen, there is 
now ample evidence of chemotherapy promoting the immune response. It has been shown that 
certain forms of chemotherapy can cause immunogenic cancer cell death and thus promote 
induction of anticancer immunity.13 
 
In the proposed study population DCVAC/PCa immunotherapy will be added to the 
chemotherapy with docetaxel and prednisone. Docetaxel is a taxane which binds to the β-
subunit of tubulin and affects microtubule polymerization, leading to cell-cycle arrest at the 
G2/M stage and subsequent cell death. In humans, there is circumstantial evidence that taxanes 
can stimulate the anti-cancer immune response. A cohort of subjects with breast cancer treated 
with taxanes showed enhanced T cell and NK-cell functions compared to subjects untreated 
with taxanes.20 
 
Furthermore, docetaxel administration considerably decreased myeloid derived suppressor cells 
(MDSC) proportion in mice models. A recent study showed that docetaxel could reverse 
MDSC-mediated immune suppression and modulate the tumor micro-environment, thereby 
improving the efficacy of immune-based therapies.21 
 
A clinical trial showing that docetaxel can be administered safely with immunotherapy without 
inhibiting immunotherapy specific T-cell responses has been performed in subjects with 
castration resistant prostate cancer. In this trial, subjects previously treated with an anti-cancer 
immunotherapy may respond longer to docetaxel compared with a control group of subjects 
receiving docetaxel alone.22,23 
 
Chemotherapy, which is broadly viewed as immunosuppressive, might to some extent boost an 
anti-tumor response.12,13 
For example docetaxel 
may have a 
relatively potent 

 
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immunomodulatory effect, enhance lymphocyte proliferation as well as the cytotoxic activity 
of natural killer and lymphokine-activated killer cells, while reducing Treg cell populations.24 
In addition, clinical studies have shown that chemotherapy can be combined with a cell-based 
immunotherapy for prostate cancer without blunting the immune response to the 
immunotherapy.25 Other studies have shown that chemotherapy administered following 
immunotherapy may enhance the immunologic response by introducing immunologically 
relevant antigens to a heightened immune system upon destruction of the tumor, thereby acting 
as a immunotherapy boost in addition to reducing tumor burden.24-26 Initiation of chemotherapy 
prior to vaccination would be an option, if we want to reduce the level of suppressive cells. 
Thus, the combination of chemotherapy with immunotherapy is an attractive strategy that merits 
clinical investigation in mCRPC. 
The strategy of Sotio’s clinical program in cancer immunotherapy is based on the assumption 
that cancer immunotherapy as a standalone treatment may be efficacious at the stage of the 
low tumor cell burden, ideally at the stage of the minimal residual disease. At advanced stages 
of the disease, cancer immunotherapy alone has little chance to affect the established 
population of tumor cells and overcome the immunosuppressive microenvironment of the 
tumor tissue. In advanced stages of the disease, immunotherapy should be combined with 
other treatment modalities that have the capacity to reduce the number of tumor cells, increase 
the sensitivity of tumor cells to the lysis by the effector cells of the immune system and to 
reduce the immunosuppression mediated by the tumor microenvironment.10,27 Studies in the 
past 5-7 years have challenged the classical view of chemotherapy as exclusively 
immunosuppressive regimen and have revealed multiple immune stimulating effects of 
conventional anticancer drugs.23 Chemotherapeutics, which are broadly viewed as 
immunosuppressive, might to some extent boost an anti-tumor response. For example taxane-
based chemotherapy may have a relatively potent immunomodulatory effect, enhances 
lymphocyte proliferation as well as the cytotoxic activity of natural killer and lymphokine-
activated killer cells, while reducing Treg cell populations.24 Other studies have shown that 
chemotherapy administered following immunotherapy may enhance the immunologic 
response by introducing immunologically relevant antigens to a heightened immune system 
upon destruction of the tumor, thereby acting as an immunotherapy boost in addition to 
reducing tumor burden.13,24-26 This led to the postulation of the concept of combined chemo-
immunotherapy that explores the capacity of the chemotherapy to reduce the number of tumor 
cells and to deplete inhibitory cells, such as regulatory T-cells.28 Chemotherapy is then 
followed, after a period of immune system recovery, by the stimulation of tumor cell specific 
effector T-cells by active cancer immunotherapy. We have determined a time window after 
the chemotherapy when the T cells regain the capacity to be stimulated in the antigen specific 
manner and the protocol design reflects those findings.  
Induction of tumor specific T-cell-mediated immune response takes time and frequency of 
tumor-specific T-cells needs to be maintained by repeated boosting. This mechanism of action 
of cancer immunotherapy has to be reflected in the clinical trial designs to ensure sufficient 
exposure of patients to the tested treatment. DCVAC/PCa should thus be administered over 
prolonged period of time, until the initiation of the next line treatment initiated for the 
confirmed radiological progression to maximize its immunostimulating potential.  
 

 
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DCVAC/PCa has been shown to induce detectable tumor-specific immune responses in-vivo 
when administered concomitantly with docetaxel.15 From ongoing phase I/II trials there is 
evidence that long-term application of DCVAC/PCa has an acceptable safety profile. Thus, 
there is a rational background that the chemo-immunotherapy approach of enhancing the 
immune response by repeated administration of DCVAC/PCa with standard of care 
chemotherapy may have an impact on the survival benefit to subjects. DCVAC/PCa is being 
considered as an add-on option for subjects requiring docetaxel and as a maintenance boosting 
of immune system after docetaxel treatment completion or discontinuation to prolong OS.  
 
 
 

 
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3 
OBJECTIVES  
This is a Phase III confirmatory study to evaluate the overall survival superiority of treatment 
with DCVAC/PCa plus Standard of Care (docetaxel plus prednisone) over placebo plus 
Standard of Care (docetaxel plus prednisone) in men with mCRPC.  
 
3.1 
Study Objectives  
 
Primary: 
The primary objective is to show superiority of treatment with DCVAC/PCa in addition to 
Standard of Care chemotherapy (docetaxel plus prednisone) over placebo in addition to 
Standard of Care chemotherapy (docetaxel plus prednisone) in men with mCRPC as measured 
by OS. 
 
Key Secondary: 
The key secondary objectives include assessments of safety, treatment group comparison with 
regards to Radiographic progression free survival (rPFS), time to prostate-specific antigen 
progression, time to first occurrence of skeletal related events (SRE).  
 
Other Secondary: 
To show clinical benefit of treatment with DCVAC/PCa plus Standard of Care over placebo in 
addition to Standard of Care with regard to time to radiographic progression or SRE, proportion 
of patients with skeletal related events (SRE).  
 
Exploratory Objective: 
Treatment group comparison for the following measures: 
Proportion of subjects requiring second line treatment introduction and time to second line 
therapy, changes in quality of life (QoL) and exploratory studies for search of potential 
biomarkers. 
 
3.2 
Study Endpoints 
 
3.2.1 
Primary Efficacy Endpoint 
Overall survival is defined as the time from randomization until death due to any cause. 
 
3.2.2 
Secondary Efficacy Endpoints  
 
The definitions of secondary endpoints are based on the PCWG2 guidelines:29  
 
1. Radiological progression free survival (rPFS) 
is defined as the time from randomization to the date of earliest objective evidence of 
either: 
o radiographic progression of bone lesions 
or 

 
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o radiographic progression of soft tissue lesions  
or 
o death due to any cause.  
2. Time to PSA progression 
is defined as the time from randomization to the date of earliest objective evidence of PSA 
progression 
3. Time to first Skeletal Related Event 
is defined as the time from randomization to the date of first skeletal related events  
 
Other Secondary efficacy endpoints: 
• 
Time to radiographic progression or SRE 
• 
Proportion of patients with Skeletal Related Events (SRE) 
 
3.2.3 
Safety Endpoints 
Safety endpoints will include incidence of adverse events, clinically significant laboratory 
abnormalities, change in vital signs and change in ECOG performance status.  
 
3.2.4 
Exploratory Endpoints 
Patient reported outcomes will include evaluation of QoL using the questionnaires FACT-P and 
EQ-5D (EQ-5D only in Europe).  
 
Proportion of subjects requiring second line treatment introduction and time to second line 
treatment introduction will be evaluated. 
 
Exploratory studies for potential biomarkers will be performed to search for parameters that 
would indicate the biological effect of trial treatment or identify subjects profiting from it.  
 
Additional exploratory studies may be conducted based on the future advances in the field of 
biomarker research. 
 
 
 

 
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4 
STUDY DESIGN 
This is a randomized, double blind, placebo controlled, multi-center, international, parallel-
group phase III study. Subjects with mCRPC who are candidates to receive standard of care 
first line chemotherapy with docetaxel plus prednisone, will be randomized 2:1 into one of two 
arms: an investigational arm (DCVAC/PCa) and a control arm (placebo) in addition to Standard 
of Care chemotherapy (docetaxel plus prednisone).  
 
If disease progression occurs on either arm of the study, the patient may be treated with 
subsequent therapy at the Investigator’s discretion (see section 6.1.2). Administration of 
DCVAC/PCa or placebo will continue until start of second line treatment. DCVAC/PCa or 
placebo administrations can continue after documented Disease Progression until the 2nd line 
treatment is started.  
 
All subjects will receive up to 15 injections of DCVAC/PCa or placebo or until refusal, 
intolerance, introduction of 2nd line treatment or death occurs. All subjects will also receive 
Standard of Care chemotherapy until refusal, intolerance, completion, disease progression, or 
death. DCVAC/PCa treatment will continue as a Maintenance Boosting Phase after Standard 
of Care chemotherapy completion, refusal, intolerance or discontinuation for other reasons. 
Subjects may be treated with subsequent non-immunological therapies at the Investigator’s 
discretion until refusal, death or study closure.  
 
After screening (up to 28 days) and within 14 days of randomization, all subjects will have 
leukapheresis procedure. For those randomized to receive DCVAC/PCa, PBMCs obtained by 
leukapheresis will be processed by ex-vivo manipulation (up to 4 weeks). All subjects 
randomized to receive placebo injections will have a placebo prepared. Manufacturing 
personnel, involved in DCVAC/PCa or placebo production process, and defined investigational 
site unblinded team members (preparing the subcutaneous injections for both treatment arms) 
are the only persons that will not be blinded. All others associated with the study, including the 
apheresis center staff, will remain blinded to the randomization. 
 
Standard of Care chemotherapy (docetaxel plus prednisone) will begin 3 to 7 days after 
completion of leukapheresis. DCVAC/PCa or placebo administration will begin approximately 
5 weeks after leukapheresis and more than 7 days after the application of second cycle of 
Standard of Care chemotherapy. DCVAC/PCa or placebo is given as subcutaneous injections 
for up to 15 doses following the study schedule (see Table 1) or until refusal, intolerance, 
introduction of 2nd line therapy, or death. Final analysis is planned when the target number of 
events is reached (657 deaths) which is anticipated to occur approximately 40 months from 
initiation of the study. 
 
 

 
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Figure 1: DCVAC/PCa Phase III study design 
 
 
 
 
1 

 
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5 
POPULATION 
Adult (age >18 years) men with histologically or cytologically confirmed adenocarcinoma of 
the prostate with clinical or radiologic evidence of metastatic disease that has progressed despite 
androgen deprivation therapy (ADT) and who already prior to study entry are candidates to 
receive first line Standard of Care chemotherapy (docetaxel plus prednisone), will be enrolled 
in this study. A total of approximately 1,170 subjects will be randomized at a 2:1 ratio to receive 
either DCVAC/PCa or placebo after introduction of the first line Standard of Care 
chemotherapy with docetaxel plus prednisone. 
 
5.1 
Inclusion/Exclusion Criteria 
The Investigator or his/her designee shall ensure that all subjects who meet the following 
inclusion and exclusion criteria are offered enrollment in the study. 
 
5.1.1 
Inclusion criteria 
 
Male 18 years and older.  
 
Histologically or cytologically confirmed prostate adenocarcinoma. 
 
Presence of skeletal, or soft-tissue/visceral/nodal metastases according to one of the 
following criteria:  
 
Confirmed pathological fracture related to the disease 
OR 
 
Confirmation of distant bone and/or soft-tissue and/or visceral metastases on CT or 
MRI scan or bone scintigraphy. 
 According to RECIST 1.1 a lymph node may be considered malignant if its short 
axis is ≥ 10 mm. 
 Note that presence of disease at the primary site alone is not considered 
metastatic disease in accordance with PCWG2 and therefore not sufficient for 
entry. 
 Scans of the screening time point must be submitted to the image review facility 
(IRF) for confirmation of presence of metastases. The IRF will return a read 
result report which will prevail over the site’s interpretation.  
OR  
 
Positive pathology report of metastatic lesion. 
 
Disease progression despite ADT as indicated by:  
 
PSA increase that is ≥ 2 ng/mL and ≥ 25% above the minimum PSA as reached 
during ADT or above the pre-treatment level, if no response was observed and 
which is confirmed by a second value 1 or more weeks later.  
 
OR 
 
Progression of measurable lymph nodes (short axis ≥ 15 mm) or visceral lesion 
measurable per RECIST v1.1 criteria30 (confirmation by IRF required); 
OR 
 
Two or more new lesions appearing on bone scan/imaging compared with a previous 
scan (confirmation by IRF required) 
 
Maintenance of castrate conditions: patients, who have not had a surgical orchiectomy, 
must continue with hormone therapy (GnRH/LHRH agonists or antagonists) to reach levels 

 
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of serum testosterone of ≤ 1.7 nmol/L (50 ng/dL). The duration of the castration period 
must be at least 4 months before screening as evidenced by combination of 
clinical/laboratory data (see section 6.8.1). 
 
Laboratory criteria: 
 
White blood cells (WBC) greater than 4,000/mm3  (4.0 x109/L) 
 
Neutrophil count greater than 1,500/mm3 (1.5 x109/L). 
 
Hemoglobin of at least 10 g/dL (100 g/L).  
 
Platelet count of at least 100,000/mm3 (100 x 109/L). 
 
Total bilirubin within normal limits (benign hereditary hyperbilirubinemias, e.g. 
Gilbert’s syndrome, are permitted).  
 
Serum alanine aminotransferase, aspartate aminotransferase, and creatinine < 1.5x 
times the upper limit of normal (ULN). 
 
Life expectancy of at least 6 months based on Investigator’s judgment.   
 
Eastern Cooperative Oncology Group (ECOG) Performance status 0-2.  
 
At least 4 weeks after surgery or radiotherapy before randomization.  
 
A minimum of 28 days beyond initiation of bisphosphonate or denosumab therapy before 
randomization. 
 
Recovery from primary local surgical treatment, radiotherapy or orchiectomy before 
randomization. 
 
Signed informed consent including patient’s ability to comprehend its contents. 
 
5.1.2 
Exclusion criteria 
 
Confirmed brain and/or leptomeningeal metastases (other visceral metastases are 
acceptable). 
 
Current symptomatic spinal cord compression requiring surgery or radiation therapy. 
 
Prior chemotherapy for prostate cancer.  
 
Patient co-morbidities: 
 
Subjects who are not indicated for chemotherapy treatment with first line Standard of 
Care chemotherapy (docetaxel and prednisone). 
 
HIV positive, HTLV positive.  
 
Active hepatitis B (active HBV defined in Section 7.6.8), active hepatitis C (HCV), 
active syphilis. 
 
Evidence of active bacterial, viral or fungal infection requiring systemic treatment. 
 
Clinically significant cardiovascular disease including:  
 
symptomatic congestive heart failure.  
 
unstable angina pectoris.  
 
serious cardiac arrhythmia requiring medication.  
 
uncontrolled hypertension.  
 
myocardial infarction or ventricular arrhythmia or stroke within a 6 months 
before screening, known left ventricular ejection fraction (LVEF) < 40% or 
serious cardiac conduction system disorders, if a pacemaker is not present.  
 
Pleural and pericardial effusion of any NCI CTCAE grade. 
 
Peripheral neuropathy having a NCI CTCAE ≥ grade 2. 

 
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 
History of malignant disease (with the exception of non-melanoma skin tumors) in the 
preceding five years. 
 
Active autoimmune disease requiring treatment. 
 
History of severe forms of primary immune deficiencies. 
 
History of anaphylaxis or other serious reaction following vaccination. 
 
Known hypersensitivity to any constituent of the DCVAC/PCa or placebo product. 
 
Uncontrolled co-morbidities including, psychiatric or social conditions which, in the 
Investigator’s opinion, would prevent participation in the trial. 
 
Systemic corticosteroids at doses greater than 40 mg hydrocortisone daily or equivalent for 
any reason other than treatment of PCa within 6 months before randomization. 
 
Ongoing systemic immunosuppressive therapy for any reason.  
 
Treatment with anti-androgens, inhibitors of adrenal-produced androgens or other 
hormonal tumor-focused treatment performed on the day of randomization (except for 
GnRH/LHRH agonists or antagonists) to exclude possible anti-androgen withdrawal 
response. This criterion is not applicable to subjects who have never responded to anti-
androgen treatment, as there is no risk of anti-androgen withdrawal response.  
 
Treatment with immunotherapy against PCa within 6 months before randomization. 
 
Treatment with radiopharmaceutical within 8 weeks before randomization. 
 
Participation in a clinical trial using non-immunological experimental therapy within 4 
weeks before randomization. 
 
Participation in a clinical trial using immunological experimental therapy (e.g., monoclonal 
antibodies, cytokines or active cellular immunotherapies) within 6 months before 
randomization. 
 
Refusal to sign the informed consent.  
 
 
 

 
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6 
TREATMENTS  
 
6.1 
Description of Treatments  
 
6.1.1 
Study drug/placebo  
During the concurrent treatment period, DCVAC/PCa or placebo is administered to the patient 
subcutaneously, every 3 weeks (+/- 7 days) concurrently with Standard of Care chemotherapy. 
DCVAC/PCa or placebo will be administered at least 7 days before or at least 7 days after the 
nearest dose of chemotherapy (Day 8-15 of chemotherapy cycle).  
 
During the Maintenance Boosting period, DCVAC/PCa or placebo is administered to the patient 
every 4 weeks (-7/+14 days) starting with the dose administered after the last Standard of Care 
chemotherapy until a maximum of 15 doses are administered (the total number incl. concurrent 
treatment period).  
 
DCVAC/PCa is a cell-based immunotherapy consisting of DCs obtained from autologous 
monocytes cultured in the presence of GM-CSF and IL-4 and pulsed with the PCa cell line 
LNCaP killed by high hydrostatic pressure (HHP). The tumor cell–pulsed DCs are then 
activated by poly I:C, a Toll-like receptor 3 (TLR-3) ligand. DCVAC/PCa induces an immune 
response against tumor cells in-vivo. 
 
The safety profile of DCVAC/PCa is described in Section 1.3.2. For additional details refer to 
the IB. 
 
The placebo will be similar enough in appearance and the syringe will be blinded adequately to 
prevent the patient and blinded staff from knowing the identity of the treatment. The placebo 
contains only freezing medium, the same used when producing DCVAC/PCa: CryoStor CS10. 
It is an aqueous, serum-free, animal protein-free balanced electrolyte solution, that includes 
various sugars, salts, and other components that provide pH buffering, oncotic/osmotic support, 
free radical scavenging, and energy substrates. It also contains 10% dimethylsulphoxide 
(DMSO). It is manufactured according to GMP with USP grade components. 
 
It is unknown if the placebo will have AEs. Subjects in both treatment arms could have potential 
sensitivity reactions to the freezing medium.  
 
6.1.2 
Standard of Care therapies 
Investigators should use authorized Standard of Care chemotherapy (docetaxel plus prednisone) 
and should reference the prescribing information provided with the product when treating the 
subjects. 
 
o 
Docetaxel in combination with prednisone or equivalent is indicated for the treatment of 
subjects with mCRPC. The recommended dose of docetaxel is 75mg/m2 intravenously after 
reconstitution and dilution. Prednisone 5mg orally twice daily or equivalent is administered 
continuously.  
o 
All subjects will receive Standard of Care chemotherapy (docetaxel plus prednisone) until 
completion, refusal, intolerance, disease progression, or death. 

 
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Following discontinuation of docetaxel and study drug/placebo, all subjects may be treated with 
subsequent non-immunological therapy at the Investigator’s discretion using the protocol 
defined list of treatment options: 
 
Defined list of second line treatment options 
The defined list of second line treatment options allowed for use in mCRPC patients after 
docetaxel failure (in alphabetic order, based on NCCN guidelines, Version 2.2013)30: 
abiraterone, cabazitaxel, docetaxel, enzalutamide, mitoxantrone, radium-223.  
 
 Abiraterone and enzalutamide represents secondary hormonal manipulation and have 
shown survival benefit in clinical trials. 
 Cabazitaxel is cytotoxic chemotherapy that has shown survival benefit when used after 
docetaxel.  
 Radium-223 has shown survival benefit in patients with bone metastases and without 
visceral metastases.  
 Docetaxel rechallenge can be used in patients who have not demonstrated definitive 
evidence of progression on prior docetaxel therapy. 
 Mitoxantrone has not demonstrated survival improvement in post-docetaxel use but 
remains a palliative option, particularly in men who are not candidates for cabazitaxel 
therapy. 
 
After failure of second line therapy, the selection of treatment options is at investigator’s 
discretion. There are some other cytotoxic agents that are used as a salvage therapy7(e.g. 
reintroduction of docetaxel, vinorelbine, vinblastine, doxorubicin, etc.). 
 
 
6.2 
How The Study Drug is supplied 
 
6.2.1 
Study drug/placebo 
Each individual dose of DCVAC/PCa or placebo is delivered to the study site in a temperature 
controlled shipping container that must be handled per the instructions in the Supply Chain 
Manual. Over the course of the study the site will receive up to 15 individual doses made 
specifically for a patient. 
 
Each individual dose contains 1mL of DCVAC/PCa or placebo in a cryovial sealed in a 
secondary package (plastic bag). Each dose is produced for a specific patient and will be labeled 
accordingly.  
 
Three separate self-adhesive labels which are identical to the primary label are included and 
will be used for labeling the syringe for administration and documentation purposes. 
The completed IMP Administration Checklist is then provided to the blinded study team 
member and this check list must be inserted into the source documentation later (see section 
6.3.1 and IMP Administration manual). 
 

 
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6.2.2 
Standard of Care therapies 
Standard of Care therapies with marketing authorization will be used for this protocol and will 
be obtained by the site as per regulatory or institutional standards. 
 
6.3 
Storage, Preparation and Administration 
 
6.3.1 
DCVAC/PCa / placebo 
 
Storage 
DCVAC/PCa or placebo will be transported to the clinical site frozen in liquid nitrogen vapors 
(referred to as dry shipper) at a temperature below -150 °C or on dry ice at a temperature below 
-50 °C (referred to as thermo box) according to the clinical site location.  
 
After dilution, the DCVAC/PCa or placebo needs to be stored at room temperature until 
administration.  
 
Preparation 
 
Prior to obtaining monocytes, patients were tested and found negative for HIV, HBV, HCV and 
Syphilis. DCVAC/PCa and placebo treatment are sterile. Refer to the IMP Administration 
manual for detailed instructions regarding the product handling and preparation. Standard 
caution should be taken to protect the Investigational medicinal product (IMP) aliquot 
(DCVAC/PCa or placebo) from contamination when preparing for administration. 
DCVAC/PCa or placebo need to be handled and administered as standard sterile subcutaneous 
medicinal preparation. 
 
Administration 
 The subcutaneous injections must be administered within 30 minutes after the product 
dilution. Diluted product must be stored at room temperature until administration. 
Caution should be taken so as not to leave the prepared dose in direct sunlight.  
 The subcutaneous injection is then divided into two 2.5 mL doses for better tolerability. 
Both injections are given in the lymph node area using 23 gauge (0.6 mm) subcutaneous 
injection needle. 
 Insert completed IMP Administration Checklist into the source documentation.  
  
6.3.2 
Study Drug Injection Sites  
The doses are repeated every 3- 4 weeks (see Table 1) and should be rotated to an alternate 
anatomical area different to the previous injection, i.e. either right axillary area and left groin 
area or vice versa (for details see IMP Administration manual). 
6.3.3 
Standard of Care therapies 
Standard of Care therapies with marketing authorizations used for this protocol will be prepared 
and stored according to the prescribing information provided with the product.    
 

 
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6.4 
Patient Numbering  
Each patient is uniquely identified in the study by a “Subject ID” consisting of a protocol 
number (SP005), the site number (Cxxx) and a subject sequential number (Bxxx). The site 
number is assigned by SOTIO to the Investigative site. Upon signing the informed consent form 
(ICF), the patient is assigned a sequential subject number by the Investigator. At each site, the 
first patient is assigned patient number 1 (B001), and subsequent subjects are assigned 
consecutive numbers (e.g. the second patient is assigned patient number 2; the third patient is 
assigned patient number 3). The Investigator or his/her staff will contact the IVRS/IWRS and 
provide the requested identifying information for the patient to register him into the 
IVRS/IWRS. Once assigned to a patient, the subject number will not be re-used.  
If the patient fails to be found eligible after all screening procedures are complete, the 
IVRS/IWRS must be notified within 3 days that the patient will not be randomized and screen 
failure will be recorded in the source documentation. Subjects may undergo up to one additional 
screening for eligibility (re-screening, see Section 6.7.1). In such occasion the subject will get 
a new „Subject ID”. 
 
6.5 
Treatment Assignment 
At Randomization visit, all eligible subjects will be centrally randomized in a 2:1 DCVAC/PCa 
to placebo allocation ratio via IVRS/IWRS. The randomization schedule is computer generated 
and will be stratified by: 
 Region (US or other) 
 Prior therapy (abiraterone or enzalutamide or neither of the two) 
 ECOG status (0 - 1 or 2) 
Although, race is not used as a stratifying factor, special considerations will be given to include 
sites with a majority of African-American subjects in order to ensure a representation of racial 
and ethnic groups.  
  
The treatment assignment will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A patient randomization list will be produced by the 
IVRS/IWRS provider using a validated system that automates the random assignment of 
treatment. The Investigator or his/her delegate will call or log on to the IVRS/IWRS and confirm 
that the patient fulfills all the inclusion/exclusion criteria. 
 
Randomization assignment will be available to the SOTIO unblinded team members who are 
responsible for the drug manufacturing and packaging. Each package of study drug will contain 
the unique identification code containing “Subject ID” and LOT number. 
 
6.6 
Treatment Blinding 
Subjects, investigational site staff, personnel performing the assessments and monitoring, 
personnel performing leukapheresis, and data analysts will remain blinded to the identity of the 
study treatment from the time of randomization until database lock, using the following 
methods:  
 
(1) Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the treatment study with the following exceptions: 
 

 
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 
SOTIO personnel that coordinate and manufacture DCVAC/PCa and placebo products.  
 
Independent statistician who will prepare information for IDMC. 
 
IDMC members will routinely review blinded data, unless a safety signal has been 
identified and IDMC has decided to unblind the relevant cases to assess the signal. 
 
Unblinded SOTIO pharmacovigilance personnel performing assessment of SAEs and their 
potential qualification as SUSARs and further distribution to regulatory bodies based on 
the treatment allocation. 
 
Site staff receiving IMP dose from shipper and preparing the DCVAC/PCa or placebo for 
diluted and ready-to-inject form. 
 
(2) The identity of the treatments will be concealed by leukapheresis procedure in both 
treatment arms, the use of study drug/placebo that are identical in packaging, labeling, and 
schedule of administration. The placebo will be similar enough in appearance and the syringe 
will be blinded adequately to prevent the patient and blinded staff from knowing the identity of 
the treatment.  
 
Unblinding will only occur in the case of patient emergencies (see Section 6.14), for regulatory 
reporting purposes and at the conclusion of the study. 
 
6.7 
Patient Treatment Sequence  
 
6.7.1 
Screen/Randomize 
All subjects will be screened for eligibility to the study for up to 4 weeks before randomization. 
Central randomization will occur on Day 1 when subjects are determined to have met all of the 
inclusion and none of the exclusion criteria. Subjects may undergo up to one additional 
screening for eligibility (re-screening). 
   
6.7.2 
Schedule leukapheresis procedure 
All subjects will undergo an evaluation for leukapheresis by technically qualified personnel 
either at the leukapheresis center or at investigational site to fulfill local requirements. This visit 
(or visits – if necessary) must be performed prior to the leukapheresis procedure itself. The 
purpose of this visit is to assess technical aspects such as the patient’s venous access (eventually 
a possibility to insert central venous catheter), to collect blood samples if required by 
legislations/regulations and to provide further information to the patient regarding the 
procedure. Venous access check will be done by technically qualified personnel. Serological 
tests will be performed according to local regulations in recommended timelines. Additional 
blood tests might be required per leukapheresis facility requirements. 
Subjects are not allowed to use ACE inhibitors 24 hours prior to leukapheresis. Calcium might 
be administered to the patient as a precaution measure to supplement Ca2+ blood levels during 
the leukapheresis procedure. All leukapheresis centers will have been approved as part of the 
study. The patient will be scheduled for the leukapheresis procedure to occur within 14 days 
after randomization and before the first dose of the Standard of Care chemotherapy. Detailed 
information is available in the relevant study manual. 
 

 
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6.7.3 
The Leukapheresis Procedure 
All subjects will undergo just one leukapheresis in a facility approved for the study. A volume 
of more than 40 mL with a minimum of 4x109 PBMCs will be obtained. Maximum volume of 
leukapheresis product is 500 mL containing suspension of PBMCs with possible addition of 
autologous plasma. Following the leukapheresis procedure the cells will be transported under 
specified and controlled conditions to the processing facility. Complete specifications on the 
leukapheresis process, relevant safety information and list of potential complications can be 
found in the relevant study manuals. The processing of the cells for the manufacturing of the 
DCVAC/PCa or placebo requires up to 4 weeks. 
 
6.7.4 
Treatment with Standard of Care chemotherapy plus DCVAC/PCa or 
placebo and consequently with DCVAC/PCa or placebo alone 
Treatment period will consist of two parts. Concurrent treatment period - first line Standard of 
Care chemotherapy with docetaxel plus prednisone administered every 21 days will begin 3 to 
7 days after the leukapheresis procedure. The initial dose of DCVAC/PCa or placebo will be 
administered subcutaneously at least 7 days after the second cycle of docetaxel, which is 
approximately 5 weeks after the leukapheresis procedure. All doses administered concurrently 
with Standard of Care (docetaxel plus prednisone) will be given in 3 week intervals (+/- 7 days). 
DCVAC/PCa or placebo will be administered at least 7 days before or at least 7 days after the 
nearest chemotherapy dose, e.g. at Day 8-15 of the chemotherapy cycle.  
After Standard of Care chemotherapy is completed or discontinued, DCVAC/PCa or placebo 
will be given in Maintenance Boosting period. Frequency of DCVAC/PCa or placebo 
application will continue in 4 week intervals with an acceptable window of - 7/+14 days for up 
to total 15 doses.   
 
After the first dose of DCVAC/PCa or placebo, the patient will be observed for 2 hours in a 
supervised out-patient setting for AEs. For the second dose and all subsequent doses of 
DCVAC/PCa or placebo administration the patient will be observed for at least 30 minutes post-
injection in a supervised out-patient setting.  
 
A significant and potentially beneficial immune response may cause transient increases in the 
size of lymph nodes or tumor masses, which could be identified as progressive disease based 
on modified RECIST 1.1 criteria.31 Additionally, currently used immunological treatments 
(e.g., ipilimumab) tend to show that despite initial signs of cancer progression there is a higher 
chance for the subjects to gain prolongation of survival. For these reasons, the application of 
DCVAC/PCa or placebo will continue irrespective of progression, however, it must be 
discontinued at the moment of introduction of 2nd line antitumor treatment. Following a 
confirmed documented radiological progression, Standard of Care chemotherapy will be 
discontinued and the second line treatment may be introduced at the Investigator’s discretion 
using the protocol defined list of second line treatments (see section 6.1.2).  
 
 
 
 
 

 
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6.8 
Ancillary Treatments 
 
6.8.1 
Androgen deprivation therapy 
All subjects who have not had a surgical orchiectomy must continue with hormone therapy 
(GnRH/LHRH agonists or antagonists) to reach levels of serum testosterone ≤ 1.7 nmol/L (≤ 
50 ng/dL). The duration of the castration period (orchiectomy or GnRH/LHRH agonists or 
antagonists) must be at least 4 months before screening of the patient into the study and continue 
throughout the entire trial. Confirmation of the castrate condition must be corroborated by the 
evidence of the first GnRH/LHRH analog administration more than 6 months before screening, 
and serum testosterone level ≤ 1.7 nmol/L measured either more than 4 months before screening 
or at screening. Secondary hormonal manipulation, if used (e.g. abiraterone, enzalutamide), 
must be discontinued on the day of randomization at the latest and may be introduced only after 
DCVAC/PCa or placebo is discontinued.  
 
6.8.2 
Rescue medication 
Basic life support equipment as defined by respective national standards of care must be 
available at sites, where application of DCVAC/PCa or placebo is performed.  
 
Investigators should comply with institutional standards of care in managing subjects who 
exhibit life-threatening symptoms while receiving treatment under this protocol. Specific 
country references to Resuscitation Guidelines such as those for the UK found on the web site 
http://www.resus.org.uk/pages/guide.htm#updates are recommended.  
 
 
Subjects having a serious allergic reaction to DCVAC/PCa or placebo must be withdrawn from 
the treatment phase of the study.  
 
6.8.3 
Other concomitant medications 
The Investigator should instruct the patient to notify the study site about any new medications 
taken from screening. All medications and significant non-drug therapies (including physical 
therapy and blood transfusions) administered after screening must be listed on the Concomitant 
Medications/Significant Non-drug Therapies eCRF. Active immunization with anti-infectious 
vaccines when appropriately indicated is allowed according to prescribing information as well 
as administration of intravenous immunoglobulins for the correction of secondary 
hypogammaglobulinemia. 
 
6.8.4 
Prohibited Medications 
Prohibited medications include: 
 
 Systemic immuno-suppressive therapy, including systemic corticosteroids at doses 
greater than 40 mg of hydrocortisone daily or equivalent, for any reason other than the 
treatment of prostate cancer. 
 Immunotherapy with other approved medications including monoclonal antibodies, 
active cellular therapies and cytokines. 
 Other investigational medicinal products. 

 
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 Concomitant anti-androgens other than GnRH/LHRH agonists or antagonists for 
maintaining castrate condition.  
 ACE inhibitors 24 hours prior to leukapheresis. 
 Concomitant use of alpha particle-emitting radioactive therapeutic agent (e.g. radium-
223), or other radioactive isotopes indicated for systemic treatment of bone metastases. 
 
6.9 
Permitted Dosing Modifications 
Administration of Standard of Care first line chemotherapy (docetaxel plus prednisone) will be 
performed according to the approved prescribing information provided with the product. The 
recommended dose of docetaxel is 75 mg/m2. Prednisone or prednisolone 5 mg orally twice 
daily (or equivalent) is administered continuously. Docetaxel should be administered when the 
neutrophil count is ≥ 1,500 cells/mm3. In patients who experienced either febrile neutropenia, 
or neutrophil count < 500 cells/mm3 for more than one week, or severe or cumulative cutaneous 
reactions, or severe peripheral neuropathy during docetaxel therapy, the next dose of docetaxel 
should be reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these 
reactions at 60 mg/m2, the treatment should be discontinued. All changes in dosage must be 
recorded in the eCRF. 
 
For the study drug DCVAC/PCa or placebo, the full dose will be administered across all 
applications and dosing modification is not applicable. Each dose during the Concurrent 
Treatment period will be administered between two chemotherapy cycles and the gap between 
DCVAC/PCa or placebo and previous and subsequent chemotherapy must be at least 7 days. If 
the chemotherapy application is delayed for any reason, DCVAC/PCa or placebo will be 
administered at least 7 days after the last chemotherapy administration. In case of acute 
infection or fever, DCVAC/PCa or placebo application has to be postponed until patient has 
recovered from the condition. When interruption of treatment is needed, DCVAC/PCa or 
placebo is allowed to be re-introduced within 12 weeks. 
 
 
6.10 
Study drug discontinuation/End of Treatment 
Subjects are expected to remain on study treatment until completion or until introduction of 2nd 
line antineoplastic therapy. After discontinuation for any reason or completion of all doses of 
DCVAC/PCa or placebo per protocol, subjects should be considered off-DCVAC/PCa or 
placebo treatment and to be evaluated at the next regularly scheduled visit within 30 days from 
the last dose of DCVAC/PCa or placebo (End of Treatment Visit). It is highly recommended to 
evaluate disease progression prior to introduction of 2nd line antineoplastic therapy if the 
decision is made before completion of study treatment. 
 
Maximum gap between two consequent DCVAC/PCa or placebo administrations should not 
exceed 12 weeks. If interruption of DCVAC/PCa or placebo lasts for more than 12 weeks, the 
study medication should be stopped. 
 
 
 

 
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All randomized patients who subsequently permanently discontinue the treatment, will still be 
followed up according to section 6.12 (even if the subject discontinued for the following 
reasons): 
 Emergency unblinding of treatment assignment when investigator or patient are 
unblinded (see section 6.14). 
 Protocol violation requiring patient withdrawal as assessed by the Investigator or the 
Sponsor. 
 Patient unable to tolerate the leukapheresis procedure. 
 Failure to produce DCVAC/PCa or placebo in the Sponsors manufacturing facilities. 
 Patients having a serious allergic reaction to DCVAC/PCa or placebo must be 
withdrawn from the treatment phase of the study. 
 
6.11 
Follow-up for toxicities 
All subjects will be followed-up for AEs at the next regularly scheduled visit following the last 
dose of treatment (End of Treatment Visit) up to 30 days from last administration of study 
medication or up to introduction of 2nd line antineoplastic therapy, whichever occurs first. An 
unscheduled visit may be added if clinically indicated. 
 
6.12 
Follow-up for survival 
Subjects for whom leukapheresis or production failed, or who have not received DCVAC/PCa 
or placebo for other reasons, will be followed up for survival only. The survival data will be 
collected every 12 weeks by directly contacting the subject (or a relative/caretaker). Subjects 
who discontinue either DCVAC/PCa or placebo treatment should enter the follow-up phase of 
the study. See Table 1 for the required assessments for these subjects during follow-up. If 
applicable, subjects should continue on 2nd line antineoplastic therapies (see section 6.1.2) for 
prostate cancer and then other therapies. All randomized patients will remain in the study and 
will be followed until ICF withdrawal, death or study closure regardless their future treatment 
and /or participation in different clinical trials. Final analysis will be performed upon reaching 
the targeted number of events. If subject refuses to return to the site for follow/up assessment, 
the investigator will make every effort to contact the subject (or a relative/caretaker) to collect 
survival information. The investigator should show “due diligence” by documenting in the 
source documents steps taken to contact the patient, i.e., dates of telephone calls, registered 
letters, etc.  
 
6.13 
Premature patient withdrawal / End of Study 
Subjects may voluntarily withdraw from the study or be discontinued at the discretion of the 
Investigator at any time. If such withdrawal occurs, or if the patient fails to return for visits, the 
Investigator shall determine the primary reason for a patient’s premature withdrawal from the 
study and record this information on the End of Study eCRF and notify the IVRS/IWRS.  
 
Subjects must be withdrawn from the study prematurely for one of the following reasons: 
 Informed consent withdrawn for continued study participation. 
 Death. 
 

 
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If premature study withdrawal occurs for any reason, the Investigator must make every effort 
to contact the patient and determine the primary reason for a patient’s premature withdrawal 
from the study and record this information on the End of Study eCRF. The End of Study visit 
assessments should be performed wherever possible; however, at a minimum, subjects will be 
contacted for a safety evaluation assessment up to 30 days from last administration of study 
medication.  
 
6.14 
Emergency unblinding of treatment assignment 
Emergency unblinding should only be undertaken when it is essential to treat the patient safely 
and efficaciously. Most often, study drug discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency code breaks are performed using the IVRS/IWRS. The study medical 
monitor will be contacted before unblinding, wherever possible, and when the patient’s safety 
is not compromised. When the Investigator contacts the system to unblind a patient, he/she must 
provide the requested patient identifying information and confirm the necessity to unblind the 
patient. The Investigator will then receive details of the drug treatment for the specified patient 
and a fax or email confirming this information. The system will automatically inform the 
SOTIO representatives that the code has been broken. 
 
There may be instances where unblinding may be required for a safety review at the request of 
the IDMC or for a Regulatory Authority. If this is not considered to be emergency unblinding, 
the assigned treatment is not revealed to the site Investigator, the study Principal Investigator, 
or the clinical or data management staff of the Sponsor or the CRO, the patient will continue 
with study treatment until protocol criteria for withdrawal are met.  
 
 
 

 
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7 
VISIT SCHEDULE AND ASSESSMENTS 
 
Screening Period 
All subjects will be evaluated for inclusion in the study during the Screening Period. Procedures 
to be performed are described in Table 1.   
 
Randomization Visit 
At the day of Randomization Visit subjects will be re-evaluated for inclusion in the study, 
relevant tests and safety information will be collected (see Table 1) and subjects who are eligible 
for the study based on screening assessments will be randomized on Day 1 as described in 
Section 6.5.  
 
Leukapheresis Evaluation and Leukapheresis Timeline 
Per section 6.7.2 and prior to the leukapheresis (not more than 7 days where required by the 
local law and regulation) procedure all subjects will undergo leukapheresis evaluation 
(laboratory tests and vein access check). Laboratory tests must be performed according to local 
law and regulations. All subjects will undergo leukapheresis procedure within 14 days after 
randomization.  
 
Concurrent Treatment Period 
During the Concurrent Treatment Period patients will receive Standard of Care chemotherapy 
with docetaxel plus prednisone plus DCVAC/PCa or placebo every 21 days. Patients will begin 
the study receiving first line chemotherapy (docetaxel and prednisone) and DCVAC/PCa 
treatment will be added after the second cycle of docetaxel. 
 
The end of the Concurrent Treatment Period starts when the first line Standard of Care 
chemotherapy has been discontinued for any reason.  
 
Maintenance Boosting Period  
During the Maintenance Boosting Period subjects will continue to receive DCVAC/PCa or 
placebo every 28 days until completion of all manufactured 15 doses or refusal, intolerance, 
introduction of 2nd line treatment or death. Based on the Investigator’s decision, the second line 
Standard of Care therapy may be introduced if considered to be beneficial. DCVAC/PCa 
administration must be discontinued in this case. The end of the Maintenance Boosting Period 
starts when the DCVAC/PCa or placebo treatment has been discontinued for any reason. 
 
End of Treatment  
The End of study treatment visit to be done within 30 days from the last application of 
DCVAC/PCa or placebo. 
 
Follow-up Period 
During the Follow-up period subjects will be off the DCVAC/PCa or placebo treatment but 
may continue Standard of Care therapy. Subjects are followed until refusal, death or study 

 
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closure. See Section 6.13 for the reasons subjects are considered to be prematurely withdrawn 
from the study.  
 
End of Study visit 
The End of Study visit occurs when the patient is withdrawn from the study for any reason. It 
is primarily captured when a subject has a documented date of death. 
 
The Visit Evaluation Schedule (Table 1) lists all of the assessments and indicates with an “X” 
the visits when they are performed. All data obtained from these assessments must be supported 
in the patient’s source documentation. Assessments that are transferred to the database 
electronically (e.g. laboratory data) are listed by test name. Please note that the Visit Evaluation 
Schedule indicates visits and evaluations to be performed under ideal circumstances. For some 
assessments (e.g. PSA and CT/MRI/bone scan), the interval between evaluations (e.g. 12 
weeks) should be observed if the visit schedule is modified for any reason. Therefore, such 
assessments might be performed at other visits than shown here.  

 
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Table 1: Visit Evaluation Schedule 
 
 
Study period 
Screening 
Randomization 
Leukapheresis 
Concurrent Treatment Period* 
Maintenance Boosting Period† 
EOT1 
Follow Up 
EOS2 
3 week cycles 
4 week cycles 
4Weeks 
12 week 
cycles 
4 weeks 
Cycle 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
1 
2 
3 
4 
5 
6 
Week of Cycle 
1 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
1 
1 
1 
1 
1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Assignment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Biochemistry  
(incl. ALP, LDH) 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PSA3 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X3 
 
TSH 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Urinalysis 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
HIV, syphilis, HTLV, 
Hepatitis B and C 
X 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Testosterone 
X16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aPTT / Quick (PT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full PE and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom directed PE 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs & weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG score 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

 
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Study period 
Screening 
Randomization 
Leukapheresis 
Concurrent Treatment Period* 
Maintenance Boosting Period† 
EOT1 
Follow Up 
EOS2 
3 week cycles 
4 week cycles 
4Weeks 
12 week 
cycles 
4 weeks 
Cycle 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
1 
2 
3 
4 
5 
6 
Week of Cycle 
1 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
1 
1 
1 
1 
1 
FACT-P questionnaire 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
EQ-5D questionnaire 
(only in Europe) 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X18 
 
 
 
 
 
 
 
X18 
 
 
X18 
 
 
X18 
X18 
 
Samples for research6 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Leukapheresis 
evaluation7 
 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis 
procedure8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DCVAC/PCa or placebo 
in process  
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
First line 
chemotherapy9,* 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
DCVAC/PCa or placebo 
s.c.injection10,† 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X11 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 X12 
Documentation of any 
SRE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease assessment14 
CT(MRI13)/bone scan 
X15 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X14 
 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival Follow-up17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
*The first line chemotherapy may be discontinued early if subject refuses or has intolerance. Subjects are then eligible to continue in the Maintenance Boosting period, 
receiving DCVAC/PCa or placebo as monotherapy in 4 weeks intervals. 

 
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†When subjects finish or stop receiving DCVAC/PCa or placebo, they complete the End of Treatment procedures within 30 days after the last dose of the study drug (End 
of Treatment Visit) and enter the Follow-up period. 
1 End of Treatment (EOT) visit procedures are performed within 30 days after discontinuation of DCVAC/PCa or placebo. 
2 End of Study (EOS) visit procedures are performed within 30 days after premature withdrawal for ICF withdrawal, death, or study closure. 
3 Until progression, introduction of 2nd line therapy or end of clinical trial, every 12 weeks. 
4 Vein access check at investigational site or by technically qualified personnel. 
5 Per local regulations for infectious diseases (HBV, HCV, HIV, HTLV, syphilis) as applicable. Additional blood tests might be required per apheresis center requirements.  
6 Blood sample for research purposes to be taken at randomization, before administration of the 5th dose of DCVAC/PCa or placebo, at EOT visit. 
7 Leukapheresis evaluation to be scheduled before leukapheresis procedure according to local law and regulations.  
8 Leukapheresis procedure to be performed within 14 days of randomization. 
9 First line chemotherapy with docetaxel plus prednisone must begin 3 to 7 days after leukapheresis. 
10 The subcutaneous injection of DCVAC/PCa or placebo must be given at least 7 days before or at least 7 days after the nearest dose of standard of care chemotherapy. 
11 Until total number of 15 doses of DCVAC/PCa / placebo, depending on number of first line chemotherapy cycles; until introduction of 2nd line chemotherapy 
12 Serious Adverse Reactions (SARs) and Adverse Events of Special Interest (AESIs) with a plausible causal relationship to investigational product. 
13 In case of sensitivity to i.v. contrast medium, the CT chest scan should be performed without i.v. contrast medium and the abdomen and pelvis should be imaged using 
MRI. 
14 Imaging will be performed every 12 weeks as close as possible to the PSA sampling until radiological progression, introduction of 2nd line therapy or end of clinical 
trial. 
15 Not earlier than 28 days before screening, and preferably not later than 14 days before randomization to allow for timely confirmation of radiographic eligibility by 
central reading. 
16 To be measured in case that historical (older than 4 months before screening) serum testosterone value doesn´t exist. 
17 Subjects for whom leukapheresis or production failed, or who have not received DCVAC/PCa or placebo for other reasons, will be followed up for survival only 
18 Every 12 weeks until progression and at 6 months and 12 months after progression. 
 
 

 
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7.1 
Patient Demographics/Other Baseline Characteristics 
Screening evaluations will occur in a period of up to 28 days from the first screening evaluation 
to randomization unless otherwise specified. The purpose of the screening period is to assure 
that subjects meet all entry criteria and that they adequately comprehend the protocol and its 
requirements. More than one clinic visit may be required in order to complete all screening 
evaluations.  
 
The screening/baseline procedures will collect the following information:  
 
 Disease History:  
o Histological or cytological diagnosis of prostate adenocarcinoma. 
o Date of initial diagnosis. 
o Staging, Gleason score and PSA level at initial diagnosis. 
o Two last historical PSA values before screening including dates 
o Details of primary treatment for prostate cancer including dates of therapy 
(radiation, surgery, steroids and/ or hormones), prior use of sipuleucel-T, abiraterone 
and enzalutamide. 
o Physician’s assessment of progression of disease to qualify for study.  
o Castration history and duration of treatment before screening. Serum testosterone 
level must be measured at screening in case that historical (older than 4 months 
before screening) serum testosterone value doesn´t exist. In such case investigator 
must document that patient started GnRH/LHRH analogs more than 6 months before 
screening. 
o Bisphosphonate or denosumab or opioid analgesic or corticosteroids use and 
duration of treatment prior to study entry. 
o History/baseline of SRE. 
 Patient Demographics – age, ethnicity, race. 
 Life expectancy based on investigator’s judgment.  
 Medical history – significant historical events or findings and any pre-existing 
conditions – history of anaphylaxis or other serious reactions following vaccination, 
history of severe forms of primary immune deficiencies. 
 Physical exam – concurrent illness, height, weight, vital signs (blood pressure, heart rate 
and temperature), peripheral neuropathy, pleural and pericardial effusions. 
 Eastern Cooperative Oncology Group (ECOG) Performance Status, Quality of life 
(QoL) questionnaires FACT-P and EQ-5D (EQ-5D only in Europe). 
 Disease assessment by CT, bone scan (historical scans can be up to 2 years old, 
screening scans can be performed within additional 4 weeks before screening period 
starts, only if results can be forwarded for central review). 
 Hematology and Biochemistry including LDH, ALP, TSH and PSA. Urine analysis will 
be performed. 
 HIV, HTLV, syphilis, HBV and HCV status. 
 Vein access check at investigational site or by technically qualified personnel. 
 

 
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7.2 
Treatments 
Standard of Care therapy treatments will be recorded in the eCRFs documenting date of therapy, 
dosage, route of administration, and reasons for dose modifications and discontinuation. 
DCVAC/PCa or placebo treatment will be recorded in the eCRFs documenting date and time 
of therapy and site of injection. Hypersensitivity reactions or other untoward events will be 
recorded in the AE eCRF page.  
 
7.3 
Efficacy 
Trial objectives and outcomes include OS, Radiographic progression free survival (rPFS), Time 
to PSA progression, Time to first skeletal related events and proportion of patients with skeletal 
related events.  
 
1. Overall survival (OS) is defined as the time from randomization until death due to any 
cause. Overall survival can be determined by collection of the date of death using 
autopsy reports, death certificates, and/or hospital/clinic records indicating date of death 
and source of information.  
 
2. Radiological progression free survival (rPFS) 
is defined as the time from randomization to the date of earliest objective evidence of 
either: 
a. radiographic progression of bone lesions 
or 
b. radiographic progression of soft tissue lesions  
or 
c. death due to any cause  
 
3. Time to PSA progression is defined as the time from randomization to the date of 
earliest objective evidence of PSA progression. 
 
4. Time to first skeletal related events is defined as the time from randomization to the 
date of first skeletal related events. Proportion of patients with skeletal related events 
is defined as the proportion of patient after randomization 
 
 
7.3.1 
Prostate-specific antigen 
PSA levels will be assessed every 12 weeks (+/-7 days) as close as possible to imaging 
assessments (see Visit Evaluation Schedule, Table 1).  
 
The evidence of PSA progression is defined as: time from randomization to the date of PSA 
absolute increase ≥ 2 ng/mL and ≥ 25% above nadir or baseline values confirmed by a second 
consecutive value obtained at least 3 weeks later. 
 

 
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7.3.2 
Soft Tissue and Bone Lesions 
7.3.2.1 
Schedule of Imaging Time points 
Imaging will be performed at screening (not earlier than 28 days before screening, and 
preferably not later than 14 days before randomization to allow for timely confirmation of 
radiographic eligibility by central reading) and after randomization at 12 week (±7 days) 
intervals. Confirmation of imaging progression is required on a follow-up imaging time point 
at earliest 6 weeks later, preferably at the following regular imaging time point date, if the 
progression occurs at week 12 and 24. After confirmation of radiological progression or after 
introduction of 2nd line therapy, no more imaging examinations of the patient will be required 
for this trial. 
  
If the patient did not progress but was removed from study treatment (EOT), the every 12 week 
schedule (+/-7 days) for imaging assessment will be followed until progression, introduction of 
2nd line therapy or end of clinical trial to assess radiological progression. It is highly 
recommended to evaluate disease progression prior to introduction of 2nd line antineoplastic 
therapy if the decision is made before completion of study treatment. 
7.3.2.2 
Mandatory Imaging Modalities at Each Imaging Time point 
 Contrast (intravenous and oral) enhanced spiral CT of the chest, abdomen and pelvis 
o In case of sensitivity to i.v. contrast medium, the CT chest scan should be performed 
without i.v. contrast medium and the abdomen and pelvis should be imaged using 
MRI. 
o Positive oral contrast media (iodine or barium) is preferred over negative oral 
contrast media (pure water or solutions of mannitol or methylcellulose). 
 Technetium bone scan of the whole body 
 
Ultrasound is not accepted for tumor evaluation. Note that the same imaging techniques must 
be used at all time points.  
 
An imaging guidance document will be provided to the sites for a detailed description of the 
imaging procedures. 
7.3.2.3 
Site Radiologist 
All scans obtained from all subjects enrolled at each site should be reviewed by the local 
radiologist who together with the Investigator will determine the local assessment of response 
and progression.  
If possible, the same radiologist/physician should perform the evaluation for the entire duration 
of the study.  
7.3.2.4 
Image Review Facility (IRF) 
All study defined imaging data must be sent to the IRF immediately after acquisition. 

 
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The IRF will quality control the imaging data quality and review them for response and 
progression. 
The specifics of the review procedure will be described in a separate Imaging Charter. 
7.3.2.5 
Review of Bone and Soft Tissue Disease 
Bone and Soft Tissue Disease will be evaluated for Progression according to the Prostate Cancer 
Working Group 2 (PCWG2) recommendations for clinical trial conduct in castration-resistant 
disease.29 The following minor modifications will be applied to the PCWG2 criteria: 
 Progressive disease (PD) of bone or soft tissue lesions must be confirmed on a second scan 
at earliest 6 weeks later, preferably at the following regular imaging time point date if the 
progression occurs at weeks 12 and 24 
 Progressive disease (PD) of soft tissue lesions will be assessed using modified RECIST 1.1 
criteria.31 The RECIST 1.1 modifications relate to the minimal dimensions of malignant 
lymph nodes and to the evaluation of disease in the prostate bed. 
 
Assessment of Bone Lesions 
Progressive disease on bone scan is considered when a minimum of two new lesions is 
observed. Defining disease progression requires a confirmatory scan performed at earliest 6 
weeks later, preferably at the following regular imaging time point date. 
 
If at the first 12-week time point two or more new lesions are observed, PD must be 
confirmed by at least two additional new lesions on the confirmatory scan. 
 
If at the 24-week time point two or more new lesions are observed, at least two of them 
must be confirmed on the confirmatory scan for calling PD. 
When progression is documented on the confirmatory scan, the date of progression recorded 
for the study is the date of the first scan that shows the change. 
 
Assessment of Soft Tissue Lesions 
Visceral and nodal disease will be evaluated according to RECIST 1.131 with the following 
modifications:  
 Nodal disease: To be considered a new malignant node or a measurable node, the 
short axis must be ≥ 15 mm and the longest diameter ≥ 20 mm. 
 Disease in the prostate bed is defined as non-measurable disease. 
 PD of Soft Tissue Lesions has to be confirmed by a confirmatory scan performed at 
earliest 6 weeks later, preferably at the following regular imaging time point date, if 
the progression occurs at weeks 12 and 24. When progression is documented on the 
confirmatory scan, the date of progression recorded for the trial is the date of the 
first scan that shows the change. 
 
The RECIST 1.1 rules and definitions to be used in this study are listed below: 
 Measurable disease at baseline 
 Threshold for lesion measurability: 
The minimum diameter which can be reproducibly measured is twice the 
reconstruction interval. For spiral CT scans of ≤ 5 mm slice reconstruction 

 
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the value is 10 mm. If larger reconstruction intervals are used (not 
recommended), the threshold value increases accordingly.  
 Visceral disease 
o Longest diameter ≥ 10 mm.  
o Disease in the prostate bed is defined as non-measurable disease 
irrespective of its size. (modification to RECIST 1.1) 
 Nodal disease  
o short axis ≥ 15 mm and  
o longest diameter ≥ 20 mm (modification to RECIST 1.1) 
 Non-measurable disease at baseline 
 Visceral disease 
o Any lesion too small to be measurable disease. 
o Truly non-measurable lesions: leptomeningeal disease, ascites, 
pleural or pericardial effusion, lymphangitic involvement of skin or 
lung. 
o Disease in the prostate bed is defined as non-measurable disease. 
(modification to RECIST 1.1) 
 Nodal disease 
o Any pathological lymph node with a short axis ≥ 10 mm but too small to 
be measurable disease. 
 New Lesions 
The finding of new lesions on follow-up time points should be unequivocal.  
For lymph nodes to be considered new disease the following size criteria will 
apply: 
o short axis ≥ 15 mm (modification to RECIST 1.1) and 
o longest diameter ≥ 20 mm (modification to RECIST 1.1) 
 
A short summary of the RECIST 1.1 evaluation procedure to be applied for the response 
evaluation of Soft Tissue Lesions is provided below. For more details please refer to the 
RECIST 1.1 publication.31 
 At baseline all lesions are classified either as target or as non-target lesions to 
estimate the baseline tumor burden. 
 Target lesions are a subset of measurable lesions. 
Up to a maximum of 5 lesions in total and a maximum of 2 per organ are 
selected and measured.  
The baseline sum of diameters (longest for non-nodal lesions, short axis for 
nodal lesions) will be calculated.  
 Non-target lesions are all other lesions. 
Non-target lesions will have their location reported. Their size does not 
contribute to the sum of diameters. 
 At each follow-up time point each lesion category will be evaluated for 
progression or non-progression 
 Target lesion Progressive Disease (PD): 

 
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o At least a 20% increase in the sum of diameters, taking as reference 
the smallest sum on study (this is not necessarily the baseline sum 
diameters). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. 
 Non-target lesion Progressive Disease (PD) 
o Unequivocal progression of existing non-target lesions. 
 New Lesion: 
o The appearance of one or more new lesions is considered progressive 
disease (PD). 
 For each follow-up time point the response outcome for each lesion category will 
be combined to an overall time point response as illustrated in the table below. 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Non-PD 
Non-PD 
No 
Non-PD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
7.3.3 
Skeletal related events 
Skeletal related events include:  
• 
radiation therapy to bone,  
• 
pathologic bone fracture,  
• 
spinal cord compression,  
• 
surgery to bone or  
• 
change in antineoplastic therapy to treat bone pain. 
 
 
7.4 
Discontinuation of first line chemotherapy 
The variability of the decision by the Investigators to discontinue first line chemotherapy with 
docetaxel plus prednisone may have an impact upon the primary endpoint of OS. 
Discontinuation of first line chemotherapy can occur for intolerance to therapy, clinical or 
radiological disease progression, and patient refusal. The Investigator will make the decision 
for discontinuation of first line chemotherapy based on all available patient information. The 
blinding of the study treatment should minimize potential bias in the selection of second line 
therapy. 
 
 
7.5 
Disease progression 
If the decision to change antineoplastic therapy is based on clinical symptoms that indicate 
disease progression e.g. obstructive uropathy attributable to cancer, skeletal related event, 
significant performance decline, increased pain requiring opioid treatment, pleural or peritoneal 

 
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effusion related to metastatic disease, fatigue, unintentional weight loss, progressive anemia 
that cannot be explained due to any other reason, these should be carefully documented. It is 
highly recommended to evaluate objective disease progression (bone and soft tissue lesions as 
per Section 7.3.2) prior to introduction of 2nd line antineoplastic therapy if the decision is made 
before completion of study treatment. 
 
In the absence of other indicators of disease progression, antineoplastic therapy should NOT be 
switched solely on the basis of a rise in PSA.  
 
7.6 
Safety 
Safety evaluations will include safety laboratory and immunological assessments, clinical 
evaluation of vital signs, physical examinations, performance status using ECOG scale, 
radiological examinations, and recording of all AEs. 
 
7.6.1 
Adverse events 
An AE is the appearance of (or worsening of any pre-existing) undesirable and unintended sign 
(e.g. tachycardia, enlarged liver), symptom (e.g. nausea, chest pain), or the abnormal results of 
an investigation (e.g. laboratory findings) occurring after signing the informed consent till 30 
days after the last dose of DCVAC/PCa or placebo (EOT) even if the event is not considered 
to be related to the study drug(s) or procedure(s).  
 
The definition used by this protocol is consistent with the international definition provided in 
ICH E2A standard: 
 
“Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment.” 
 
All Investigators should follow the protocol and the local regulations. The attending physician 
is responsible for describing, diagnosing and treating all AEs in accordance with the best 
standards of medical care. 
 
Please refer to Section 6.1 and 7.2 for the protocol-specific definitions of study drug and study 
procedures. 
 
AEs will be assessed according to the NCI Common Toxicity Criteria for Adverse Events 
(CTCAE) version 4.03. If NCI CTCAE grading does not exist for an AE, the severity of mild, 
moderate, severe, life-threatening and death, or grades 1 – 5, will be used. 
 
AEs occurring before starting study treatment but after signing the ICF are also collected and 
recorded on the Adverse Event eCRF. This includes AEs observed before, during and after 
study procedures (e.g. screening, leukapheresis). All SAEs must be additionally documented 
on a “Serious Adverse Event Report Form”. 
 

 
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Abnormal laboratory values, vital signs or test results constitute AEs only if they are considered 
clinically significant, in particular if accompanied by clinical signs or symptoms, require 
therapy or another medical intervention (e.g. hypokalemia that requires saline substitution), lead 
to change in medication dosing or administration, or require that the patient changes the study 
schedule. Abnormal hematological laboratory values should be recorded on the Adverse Events 
eCRF under the signs, symptoms or diagnosis associated with them (e.g. neutropenia, Grade 2). 
In case that laboratory value or vital sign is a sign of a medical condition, the condition should 
be reported as an AE and not the sign. 
  
Surgical procedures are not AEs but therapeutic measures for conditions that require surgery. 
Therefore, the condition for which the surgery is required has to be reported as an AE. Pre-
planned surgery (before signing off ICF) or other interventions permitted by the study protocol 
and the conditions leading to these measures are not AEs. 
 
The occurrence of AEs will be recorded on an ongoing basis and patients will be asked 
specifically whether they have noticed any unexpected or unusual symptoms at each scheduled 
or unscheduled visits. AEs also may be detected when they are volunteered by the patient during 
or between visits or through physical examination, laboratory test, or other assessments. Reports 
from patient relatives or caregivers should be recorded, once verified.  
 
If possible, each AE should be evaluated to determine: 
 AE term or description of the AE in medical terms (not as reported by the patient) 
 The severity grade (grade 1-5 as listed in NCI CTCAE v4.03) 
 Its causal relationship to the IMP, first line chemotherapy (suspected/not suspected) and 
study procedure of leukapheresis 
 Event duration including start date and end date, or if continuing at End of Treatment (EOT) 
or End of Study (EOS) visits 
 Action taken with the IMP due to reported event (no action taken; delay of further 
application; permanently discontinued; other) 
 Action taken with first line chemotherapy due to reported event (no action taken; dose 
adjusted; dose interrupted; delay of further application; permanently discontinued) 
 Other action taken (hospitalization required; change in concomitant medication; medical 
procedure or intervention required; other or unknown). 
 Event seriousness (serious or non-serious): a serious adverse event (SAE) is any untoward 
medical occurrence that at any dose fulfills one or more of the following criteria: 
 
Results in death. 
 
Is immediately life-threatening.  
The term “life-threatening” in the definition of serious refers to an event in which 
the patient was at immediate 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. 
 
Results in persistent or significant disability/incapacity. 
 
Is a congenital anomaly/birth defect. 

 
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 
Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 
Routine treatment or monitoring of the studied indication including 
hospitalization due to trial related procedures (e.g. leukapheresis) not 
associated with any deterioration of patient´s status. 
 
Elective or pre-planned treatment (prior to signing the informed consent form) 
for a pre-existing condition that is unrelated to the indication under study and 
has not worsened since signing the informed consent. 
 
Treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions for an SAE and not resulting in hospital admission. 
 
Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition. 
 
Underlying disease progression and events which are unequivocally related to 
the disease progression. 
 
Is other medically significant event, i.e., defined as an event 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 to prevent 
one of the outcomes listed above. 
 
Hospitalization is defined as an in-patient overnight stay that can be shorter than 24 hours. 
 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 8.1. 
 
If an AE (SAE) increases in severity, the event will be reported at the higher severity grade 
or frequency as a new AE (SAE). The onset date of the new AE will be the date that the 
severity increased. A decrease in severity should not be reported as a new AE. 
 
All AEs should be acted upon. Such acts may include changes in study drug treatment including 
possible interruption or discontinuation, starting or stopping concomitant treatments, changes 
in the frequency or nature of assessments, hospitalization, or any other medically required 
intervention. 
 
AEs causally not related to the IMP / procedure will be monitored (followed-up) until 
resolution, stabilization (becoming permanent condition) or the end of the clinical trial. 
Clinically relevant laboratory abnormalities will be followed-up until they return to normal or 
become stabilized (permanent condition).  
 
Any AE which is or might be related to the IMP / procedure as well as all SAEs will be 
followed-up until the event is resolved or stabilized (permanent condition).  
 
AE assessment should be made at each visit (or more frequently, if necessary) of any changes 
in diagnosis, severity, suspected relationship to the IMP, procedure or first line chemotherapy, 
interventions required to treat the event, and its outcome. 

 
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Information about adverse reactions (causally related events) already known for the 
investigational product can be found in the Investigator´s Brochure (IB) or will be 
communicated between IB updates in the form of Dear Investigator Letter. Basic information 
will be included in the patient informed consent and should be discussed with the patient during 
the study as needed. 
 
7.6.2 
Physical examination, weight, height 
Physical examinations will be performed by a licensed physician (or physician’s assistant or 
nurse practitioner) at screening. Symptom-directed exams will be performed on Day 1 of each 
cycle of Standard of Care chemotherapy and each application of DCVAC/PCa or placebo until 
End of Treatment visit and may be performed by a licensed physician, NP, PA, or nurse. All 
examinations should assess the patient for clinical signs of autoimmune disease. 
 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) should be measured at Screening, and weight will be measured at each dosing 
visit of Standard of Care chemotherapy during Concurrent treatment period and at each 
DCVAC/PCa or placebo administration visit in the Maintenance Boosting period and at the End 
of Treatment Visit. 
 
7.6.3 
Vital signs 
Vital signs (body temperature, sitting blood pressure and sitting pulse) will be measured at 
Screening and at each dose of Standard of Care chemotherapy and DCVAC/PCa or placebo as 
well as at End of Treatment Visit. 
Measurements of heart rate, body temperature, blood pressure and respiratory rate will be made 
after the patient has been resting supine for a minimum of 5 minutes. Subjects will be closely 
monitored during and for up to 2 hours following their first DCVAV/PCa or placebo 
administration and for 30 minutes following each subsequent administration. 
 
7.6.4 
Performance status 
Eastern Cooperative Oncology Group (ECOG)32 performance status will be measured at 
Screening, at Randomization, and on Day 1 of each cycle of Standard of Care chemotherapy 
and each injection of DCVAC/PCa or placebo and at the End of Treatment Visit. 
 
ECOG Performance status should be documented according to Table 2. 
 
 

 
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Table 2: ECOG performance status scale 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g. light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
7.6.5 
Laboratory evaluations 
The standard clinical laboratory analysis described below is to be performed by a central 
laboratory according to the Visit Evaluation Schedule, outlined in Table 1 and will be 
documented in the eCRF. Details on the collections, shipment of samples and reporting of 
results by the central laboratories are provided to Investigators in the Laboratory Manual.  
 
More frequent evaluations may be performed at the Investigator’s discretion if medically 
indicated; results should be recorded on the Unscheduled Visit eCRFs. Due to unanticipated 
circumstances, if at any time a patient has laboratory parameters obtained from a local 
laboratory, SOTIO must be provided with a copy of the certification and a tabulation of the 
normal ranges for that laboratory. 
  
Laboratory values that are out of reference ranges should be evaluated for their clinical 
significance. Abnormal laboratory values or test results that constitute AEs or underlying 
conditions should be recorded together with the respective AEs or underlying diagnosis. Only 
laboratory abnormalities that are considered clinically significant e.g. due to induction of 
clinical signs or symptoms, lead to a change in medication dosage or administration, requiring 
concomitant therapy, or other medical intervention (e.g. hypokalemia that need saline 
substitution or hematologic abnormality that requires cytokine treatment) or require that the 
patient changes the study schedule should be recorded on the AE eCRF page. Whenever 
possible, a diagnosis, rather than a symptom should be provided on the AE eCRF page (e.g. 
anemia instead of low hemoglobin). 
 
It should be noted that severity and seriousness are different criteria for AE evaluation. 
Therefore, grade 3 and grade 4 laboratory events (evaluated as per NCI CTCAE v4.03) do not 
automatically classify as SAEs unless they meet seriousness criteria as defined in section 7.6.1 
or as per Investigator’s discretion.  
 

 
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7.6.5.1 
Hematology 
Hematologic tests include: a complete blood count (CBC) consisting of red blood cells (RBCs), 
a total WBC with differential (total neutrophil, lymphocyte, monocyte, eosinophil, and basophil 
counts), hemoglobin, hematocrit, and platelet counts.  
 
Hematology will be collected every 3 weeks (or Day 1 (-3 days) of each chemotherapy cycle) 
during the Concurrent Treatment Period with DCVAC/PCa or placebo and first line 
chemotherapy with docetaxel plus prednisone. Should first line chemotherapy be discontinued 
hematology should continue to be collected every 4 weeks (-7days/+14 days) until the 
discontinuation of DCVAC/PCa or placebo.   
 
In the Follow-up period when the patient is no longer receiving DCVAC/PCa or placebo, 
hematology will be collected once at End of Treatment Visit. More frequent evaluations may 
be performed at the Investigator’s discretion if medically indicated; results should be recorded 
on the Unscheduled Visit eCRFs. 
 
7.6.5.2 
Coagulation 
Coagulation tests (aPTT and Quick) should be drawn at screening for evaluation purposes to 
leukapheresis. 
 
7.6.5.3 
Biochemistry 
Biochemistry includes Na+, K+, Cl-, Ca2+, glucose, AST, ALT, ALP, LDH, bilirubin, creatinine, 
uric acid, CRP, total protein, and albumin.  
 
Biochemistry will be collected every 3 weeks (or Day 1 (-3 days) of each chemotherapy cycle) 
during the Concurrent Treatment Period with DCVAC/PCa or placebo and first line 
chemotherapy with docetaxel plus prednisone.  
Should first line chemotherapy be discontinued, biochemistry should continue to be collected 
every 4 weeks (-7days/+14 days) until the discontinuation of DCVAC/PCa or placebo. 
TSH will be obtained every 12 weeks.  
In the Follow-up Period when the patient is no longer receiving DCVAC/PCa or placebo, 
biochemistry will be collected once at End of Treatment Visit. More frequent evaluations may 
be performed at the Investigator’s discretion if medically indicated; results should be recorded 
on the Unscheduled Visit eCRFs. 
 
7.6.5.4 
Urinalysis 
Urinalysis including dipstick analysis (pH, protein, glucose, ketones, bilirubin, blood, leucocyte 
esterase) will be collected every 6 weeks (+/-7 days) during the Concurrent Treatment period 
and every 12 weeks (-14/+7 days) in Maintenance Boosting period. 
In the Follow-up Period when the patient is no longer receiving DCVAC/PCa or placebo, 
urinalysis will be collected once at End of Treatment Visit. A microscopic (WBC/high power 
field (HPF), RBC/HPF, and any additional findings) exam need only be performed if the 
urinalysis result is abnormal. 
 

 
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7.6.6 
Pregnancy  
Pregnancy outcomes must be collected for a female partner of the patient administered the 
investigational product until 30 days after the last administration of DCVAC/PCa or placebo. 
 
7.6.7 
Radiological examinations 
Please refer to sections 7.3.2 and 7.3.3. 
  
7.6.8 
HIV, HTLV, syphilis, Hepatitis B and C 
Before randomization, subjects will be tested for HIV. Subjects with positive HIV results at 
screening are excluded from the study. Should the patient refuse testing, his participation will 
be terminated in the screening phase. 
 
National and local guidance and regulations should be followed for HIV testing, additional 
testing before leukapheresis may be required. Investigators should follow national guidelines 
on reporting and patient referral for follow-up. 
 
Before randomization subjects will be tested for HTLV. Subjects with positive HTLV results 
at screening are excluded from the study. Should the patient refuse testing, his participation will 
be terminated in the screening phase. National and local guidance and regulations should be 
followed for HTLV testing. An additional test before leukapheresis may be required based on 
local regulation. 
 
At screening, subjects will be tested for HBV markers - HBs Ab, HBs Ag, and anti-HBc Ab. 
Patients with positive HBs Ag at screening have evidence of active disease and are directly 
excluded from the study participation. Eligibility of patients with positive HBs Ab and/or anti-
HBc Ab, must be confirmed with the medical monitor and leukapheresis center first. National 
and local guidance and regulations should be followed for HBV testing (or clinically equivalent 
test). An additional test before leukapheresis may be required. 
 
Before randomization subjects will be tested for HCV Ab and HCV RNA-PCR test at Screening 
(depending on local regulations). Subjects with detectable HCV RNA at screening and evidence 
of active disease are not eligible. National and local guidance and regulations should be 
followed for HCV testing. An additional test before leukapheresis may be required. 
 
Before randomization subjects will be tested for syphilis. Subjects with positive syphilis results 
at screening and evidence of active disease are excluded from the study. Should the patient 
refuse testing, his participation will be terminated in the screening phase. National and local 
guidance and regulations should be followed for syphilis testing. An additional test before 
leukapheresis may be required. 
  
 
 
 

 
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7.6.9 
Cardiac examinations 
 
7.6.9.1 
Electrocardiogram (ECG) 
There are no required ECGs for this study. The Investigator should follow institutional 
guidelines and best clinical practice when assessing the suitability of the patient for 
leukapheresis procedure, and administration of trial treatment, including the assessment of 
cardiac function with ECGs. 
 
7.6.9.2 
Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
The patient’s medical records should be reviewed for evidence of cardiac disease of myocardial 
infarction or ventricular arrhythmias or stroke within a 6 month period prior to inclusion. This 
also includes known LVEF < 40% or serious cardiac conduction system disorders if a 
pacemaker is not present. MUGA scans or echocardiograms are not required at baseline 
screening to rule out evidence of cardiac co-morbidity. 
 
7.7 
Patient-Reported Outcomes 
For the purpose of determining the effect of treatment on QoL the patient-reported 
questionnaires FACT-P and EQ-5D (EQ-5D only in Europe) will be utilized for this study (see 
Section 14.1). The questionnaire FACT-P will be completed by the patient at screening, on Day 
1 before the first chemotherapy and every 6 weeks during the Concurrent Treatment period and 
every 4 weeks during Maintenance Boosting period, and at the End of Treatment visit. The 
questionnaire EQ-5D will be completed by patients in Europe at screening, on Day 1 of Cycle 
3 of the Concurrent Treatment period and then every 12 weeks until disease progression (e.g. 
under ideal circumstances during the Concurrent Treatment period on Day 1 of Cycle 7, during 
the Maintenance Boosting period on Day 1 of Cycle 1 and on Day 1 of Cycle 4, at the End of 
Treatment visit, and at visits during the Follow-up period). The questionnaire EQ-5D will also 
be completed at 6 months and 12 months after disease progression either by the patient or by 
the Investigator based on information provided by the patient during follow-up telephone 
contacts. 
 
7.8 
Pharmacokinetics 
Pharmacokinetic samples will not be drawn for this study. 
 
7.9 
Biomarkers 
See section 7.3.1 for section on PSA. 
 
7.10 
Exploratory studies for search of potential biomarkers  
The purpose of those exploratory studies is to search for parameters that would indicate the 
biological effect of trial treatment or identify subjects profiting from it. Blood samples for 
exploratory studies will be collected at Randomization, prior to the 5th dose of DCVAC/PCa or 
placebo, and at the End of Treatment Visit. Samples will be processed at the central lab and 
cryopreserved. Upon request, samples will be shipped to SOTIO facilities and analyzed.  
The list of planned exploratory immune response studies includes:  

 
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- 
Monitoring of circulating tumor cells in the peripheral blood 
- 
Analysis of the immune cells subsets in the peripheral blood (myeloid dendritic cells, 
plasmacytoid dendritic cells, CD4 T cells, CD8 T cells, CD19 B cells, NK cells, 
activated HLA-DR+ T cells) 
- 
Monitoring peripheral blood FoxP3+ regulatory T  
- 
Monitoring of myeloid derived suppressor cells  
- 
Quantification of tumor antigen specific T cells in the peripheral blood by intracellular 
staining for IFN-, IL-2 and TNF 
- 
Quantification of PSA, PSMA and NY-ESO1 specific CD8 T cells in the peripheral 
blood by tetramer staining in HLA-A2 positive subjects 
 
Genomic studies may be performed, if the patient consented to participate in pharmacogenomic 
research. A separate patient information sheet and/or consent form is to be presented to the 
patient. Consent to participate in pharmacogenomic research is optional and not a prerequisite 
for entry into the study. 
 
Peripheral blood samples will be used for the isolation of nucleic acids (DNA or RNA). Purified 
genomic DNA (gDNA) will then be fragmented, and a gDNA library will be prepared. Regions 
of gDNA will be sequenced using appropriate next generation sequencing techniques. For the 
purpose of gene expression profiling the total RNA will be purified and reversely transcribed 
into the complementary DNA (cDNA). cDNA will be used for gene expression profiling and 
for the detection of expression levels of potential cancer related genes. RNA samples can also 
be used as a template for RNA sequencing techniques. 
 
The aim of the genomic studies is to identify any genetic alterations as well as new potential 
biomarkers that could be used for evaluation of risk of disease progression in patients with 
prostate cancer and for the identification of those patients, who could benefit from cancer 
immunotherapy.  
 
Additional exploratory studies may be conducted based on the future advances in the field of 
biomarker research. Performing of the above mentioned experimental studies is subject to the 
availability of sufficient number of peripheral blood mononuclear cells from subjects. 
Complete instructions for collection and processing will be provided in a study Laboratory 
Manual. 
 
Clinical signs of possible autoimmune disease will be assessed during each physical exam. If 
there is any suspicion of autoimmune disease at any time during the study, appropriate 
laboratory evaluation should be performed at the Investigator’s discretion. 
 
 
 
 

 
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8 
SAFETY MONITORING 
 
8.1 
Serious adverse event reporting 
Investigator or any investigational site staff must immediately (at the latest within 24 hours of 
awareness) notify / report to pharmacovigilance department all SAEs, regardless of suspected 
causality. All SAEs must be reported from the date of the patient signing the informed consent 
form until 30 days after the last administration of DCVAC/PCa or placebo (EOT).  
 
Recurrent episodes and complications of reported SAE must be also reported within 24 hours 
of the Investigator receiving this information, if seriousness criteria have been met. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. The SAE must be 
documented and medically assessed by the Investigator. 
 
If the investigator detects an SAE in a patient after the EOT, i.e. after 30 days from the last 
administration of the investigational product, and considers the event causally related to the 
IMP, this event has to be reported within 24 hours of learning of its occurrence. 
 
Serious AE information is collected and recorded on the Serious Adverse Event (SAE) Report 
Form. The Investigator must complete the electronic SAE Report Form in English, and submit 
the completed and signed form via eCRF (EDC system) within 24 hours. The SAE notification 
will be delivered to Pharmacovigilance Department. 
 
In case of any issues related to electronic SAE reporting where an electronic SAE Report Form 
cannot be completed in eCRF and forwarded by the Investigator within 24 hours of awareness, 
a paper SAE Report Form has to be completed instead and this report has to be  forwarded to 
SOTIO Pharmacovigilance using the contact details below:  
 
Fax: +420 224 175 498 or local toll free fax lines 
Email: safety.viable@sotio.com 
Phone:  +420 725 385 443 
Address: SOTIO a.s., Jankovcova 1518/2, 170 00 Prague 7, Czech Republic 
 
New or additional information concerning SAE has to be reported as a follow-up report within 
same timelines and using the same route as noted above to SOTIO Pharmacovigilance by 
completing SAE Report Form stating that this is a follow-up to the previously reported SAE. 
The follow-up information should describe additional or new medically relevant information, 
whether the event has resolved or continues, if and how it was treated and whether the patient 
continued or withdrew from study participation.  
 
If serious adverse reaction is not listed in the IB, i.e. unexpected and causally related to the 
investigational product, the sponsor may urgently require further information from the 
Investigator due to regulatory reporting obligations. 

 
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8.1.1   
Serious Adverse Events related to disease progression 
Progression of underlying disease or AEs unequivocally related to disease progression in line 
with the study protocol (see section 7.5), regardless of their outcome and regardless whether 
they otherwise would fulfill seriousness criteria, do not need to be reported as SAEs. However, 
these events have to be captured on AE eCRF page as non-serious events. If the patient was 
hospitalized due to PD related event this must be marked on AE eCRF page.  
 
An SAE must be reported only if there are clinical signs / symptoms that cannot be without 
doubt associated to the underlying disease progression. 
 
Events with fatal outcome that are unequivocally related to progression of underlying disease 
are excluded from SAE reporting and expedited reporting as SUSARs. Overall survival is the 
primary endpoint of the trial. Therefore, it is essential to complete the End of Study Information 
eCRF page to capture the death information. If a patient dies due to the progression of 
underlying disease the EOS eCRF page should include the EOS reason as ‘Death’ and the cause 
of death must be reported as ‘Disease Progression’. 
8.1.2  
Adverse Events of Special Interest 
Adverse Events of particular importance to product’s ongoing safety and scientific monitoring 
are referred as AEs of Special Interest (AESIs). These events require ongoing monitoring and 
rapid communication by the investigator to the sponsor. 
 
SAE report form is used for reporting of AESIs. AESIs have to be reported within the same 
timelines as SAEs. Further details are specified in relevant study manual. 
 
The following AESIs must be reported: 
1. Patient’s premature discontinuation from the DCVAC/PCa or placebo treatment due to 
an AE (drop-out). 
2. Systemic allergic reactions related to IMP administration (other than local inflammatory 
reaction or irritation at injection site). 
3. Severe systemic infections related to IMP administration (e.g. sepsis due to transmission 
of infectious agents). 
4. Secondary malignancy. 
5. Autoimmune disorder (only symptomatic / clinically relevant). 
 
Only AESIs with plausible causal relationship to investigational product must be reported after 
30 days from the last IMP administration (EOT). 
8.1.3  
Pregnancies 
Men who are fertile must use a medically accepted birth control during the study and for 30 days 
after the last administration of investigational product. If their partner becomes pregnant within 
30 days after the last administration of DCVAC/PCa or placebo, the patient must inform their 

 
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study doctor without delay. Pregnancy outcomes must be collected for the female partners of 
any males administered DCVAC/PCa or placebo. Consent to report information regarding these 
pregnancy outcomes should be obtained from the mother. 
 
Every new pregnancy of female partner of a study patient and the outcome of the pregnancy 
has to be reported via a ‘Pregnancy Data Collection Form’ (hard copy) which must be submitted 
within 24 hours of learning of its occurrence using the same route and timelines as described 
for SAEs. 
 
 
8.2 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (IDMC) will be constituted prior to the 
randomization of the first patient. It is expected that the IDMC will consist of five members 
including one statistician. The IDMC will operate according to IDMC Charter which will be 
developed prior to the start of the study. The IDMC Charter will outline the data format and the 
process for all data tabulations that will be submitted to the IDMC for their review. The Charter 
will also describe the roles and responsibilities of the IDMC members and the timing and scope 
of all IDMC meetings.  
 
The purpose of the IDMC will be to provide an independent mechanism for ongoing review of 
key adverse events and SAEs. As will be noted in the IDMC Charter, all meetings of the IDMC 
will be confidential and there will be no data dissemination to sponsor representatives. 
In addition, the IDMC will monitor the DCVAC/PCa or placebo manufacturing failure rate in 
the context of the rate of lost to follow-up (LTF) subjects. The LTF rate is assumed to be 3% 
for the study. Should the rate of LTF be higher than expected, the IDMC may suggest trial 
modifications.  
The IDMC may make these recommendations to SOTIO:  
 
 
To continue the trial as planned without modification (e.g. no safety issues, ethical to 
continue the trial as planned). 
 
To continue the trial with modification (e.g. ethical to continue the study but 
recommend an amendment to the protocol or incorporate an additional safety interim 
analysis before the next scheduled analysis). 
 
To halt enrollment pending discussions with SOTIO. 
 
To stop the trial (e.g. serious safety concerns precluding further study treatment). 
 
If the study is recommended to continue by the IDMC, no details about the results of the 
current analysis will be revealed until the end of the study. 
 
 
 

 
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9 
DATA REVIEW AND DATA MANAGEMENT 
 
9.1 
Site Monitoring 
Before study initiation, at a Site Initiation Visit (SIV) or at an Investigator’s meeting, SOTIO 
personnel (or designated CRO) will review the protocol and eCRFs with the Investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol and to Good Clinical Practice (GCP), the progress of enrollment, and to ensure that 
study drug is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
 
The Investigator must maintain source documents for each patient in the study recruited at the 
relevant site, consisting of case and visit notes (hospital or clinic medical records) containing 
demographic and medical information, laboratory data, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The Investigator must also keep the original ICF signed by the patient (a second 
signed copy original is given to the patient). 
 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. SOTIO monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
 
9.2 
Data Collection 
For studies using EDC, the designated Investigator site staff will enter the data required by the 
protocol into the eCRF using fully validated software that conforms to 21 CFR Part 11 and 
EMA/INS/GCP/454280/2010 requirements. Designated Investigator site staff will not be given 
access to the EDC system until they have been trained. Automatic validation programs check 
for data discrepancies in the eCRFs and, by generating appropriate error messages, allow 
modification or verification of the entered data by the Investigator staff before transfer of data 
to SOTIO (or designated CRO). After database lock, the Investigator will receive a CD-ROM 
or paper copies of the patient data for archiving at the investigational site. 
 
9.3 
Database Management and Quality Control 
Data will be entered into the study database by the Investigator/Study Coordinator at each site. 
 
SOTIO personnel (or designated CRO) will review the eCRFs entered by investigational staff 
for completeness and accuracy and instruct the site personnel to make any required corrections 
or additions. Queries are sent to the investigational site within the EDC system. Designated 
Investigator site staff is required to respond to the query and make any necessary changes to the 
data. If the electronic query system is not used, a paper DQF will be faxed to the site.  Site 

 
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personnel will complete and sign the faxed copy and fax it back to SOTIO Data Management 
personnel (or designated CRO) who will make the correction to the database if required. In 
addition the signed original and resolved DQFs must also be sent to SOTIO Data Management 
(or designated CRO). Copies of the resolved DQF are kept with the CRFs at the Investigator 
site. 
 
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history/current medical conditions and AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Central 
laboratory samples and/or data will be processed centrally and the results will be sent 
electronically to SOTIO (or a designated CRO). 
 
Randomization codes and data about all study drug dispensed to the patient will be tracked 
using an IVRS/IWRS. The system will be supplied by a vendor(s), who will also manage the 
database. The database will be sent electronically to SOTIO personnel (or designated CRO). 
 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the database has been declared to be complete and 
accurate, it will be locked.  
 
 
 
 

 
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10 
STATISTICAL METHODS AND DATA ANALYSIS  
The details of the statistical analyses to be performed on the collected data will be described in 
a separate Statistical Analysis Plan. This statistical considerations section is focused on the 
primary analysis. 
 
10.1 
Analysis Populations 
There are 4 analysis populations. The definitions and criteria provided hereinafter will be 
updated and possibly detailed in the Statistical Analysis Plan during the data review. 
 
All Randomized Subjects (ARS) 
The ARS is a set of subjects who entered the study and who were randomized. The ARS will 
be used for a summary of demographic and other baseline characteristics.  
 
Safety Population 
The Safety population will comprise all subjects who received first-line chemotherapy and/or 
at least one dose of treatment with DCVAC/PCa or placebo and will be based on the actual 
treatment received if this differs from that to which the subject was randomized. This population 
will be used for the analysis of safety data.  
 
Intent-to-Treat Population (ITT) 
The ITT population is a subset of all randomized subjects who had at least one baseline 
assessment. ITT will be the primary efficacy population. 
 
ITT subjects will be analyzed according to their randomized study medication. 
 
According to Section 6.10 patients will be withdrawn from treatment, or not receive treatment, 
due to:  
 Emergency unblinding of treatment assignment when investigator or patient are 
unblinded.  
 Protocol violation requiring patient withdrawal as assessed by the Investigator or 
Sponsor. 
 Patient unable to tolerate the leukapheresis procedure. 
 Failure to produce DCVAC/PCa or placebo in the Sponsors manufacturing facilities. 
 Patients having a serious allergic reaction to DCVAC/PCa or placebo must be 
withdrawn from the treatment phase of the study. 
 
Patients with emergency unblinding and patients with protocol violations will be included in 
the ITT population and analyzed accordingly. Patients who have not started DCVAC/PCa or 
placebo treatment due to leukapheresis or manufacturing failure will also be included in the 
ITT population, however censored on Day 1 for the analysis of time to event endpoints, 
including the primary analysis of OS.  
 
 
 

 
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Per Protocol Population (PP) 
The PP population is a subset of the ITT and includes all subjects who are characterized by 
following criteria: 
 
 All subjects who have at least one post baseline assessment. 
 All subjects who do not have any major protocol violations that would affect the 
endpoints being assessed. 
 All subjects randomized to a treatment who received at least eight doses of 
DCVAC/PCa or placebo.  
 Any other criterion as deemed appropriate will be listed in the Statistical Analysis 
Plan.  
 
The major protocol violations and detailed reasons for excluding subjects from per protocol set 
will be fully defined and documented before breaking the blind of the specific trial. PP 
population will be analyzed according to their actual study medication. The PP population is 
the secondary efficacy population. 
 
10.1.1 
Patient Demographics and other Baseline Characteristics 
Summary statistics of demographics, history and stage of prostate cancer, medical history, and 
other baseline characteristics will be presented by treatment group. A separate summary will be 
provided for patients with leukapheresis or manufacturing failure. 
 
10.1.2 
Treatments 
Subjects who have received a different dose of a study medication than that planned in the study 
protocol will be listed including information on all doses actually received. 
 
Concomitant medications will be coded using the current WHO Drug Dictionary. The number 
and percentage of subjects who used concomitant medications will be presented by Anatomic 
Therapeutic Class (ATC) levels 1 and 2 and by treatment group. 
 
10.2 
Primary Efficacy Analysis 
 
10.2.1 
Primary Efficacy Endpoint 
Survival time, defined as the time from randomization until death due to any cause, is the 
primary endpoint. The primary efficacy analysis will be done with the ITT population.  
 
10.2.2 
Statistical Hypothesis, Model and Method of Analysis 
The primary endpoint in this study is OS.  
 
The primary hypothesis testing is to demonstrate that the treatment with DCVAC/PCa in 
addition to Standard of Care chemotherapy (docetaxel plus prednisone) is statistically 
significantly different from the treatment of Standard of Care chemotherapy (docetaxel plus 
prednisone) versus the null hypothesis of no difference between two treatment arms. 
 

 
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The primary efficacy analysis is a stratified log-rank test. Assuming an exponential distribution, 
a total of 657 deaths is required with approximately 80% power to detect a hazard ratio of 0.792 
in favor of the DCVAC/PCa group (median survival of 24 months for the DCVAC/PCa group, 
19 months for the control group) using a 2-sided log-rank test at a 5% overall significance level 
(i.e. alpha of 0.05). A total of 1170 patients will be enrolled in a 2:1 ratio (i.e., DCVAC/PCa vs. 
placebo equal to 2:1), an enrollment period of approximately 18 months, and total study 
duration of approximately 40 months to observe the required event-driven timeframe of 657 
total events for the final analysis. If the anticipated 657 events are not attained during the trial 
timeline, the study could be prolonged by SOTIO. 
 
Patients will be randomized in a 2:1 ratio, stratified by region (US vs other), prior therapy 
(abiraterone or enzalutamide or neither of the two) and ECOG score (0, 1 vs 2). 
 
The overall type I error rate will be controlled at 0.05. At the final analysis, a final p-value of ≤ 
0.0455 is required to be considered statistically significant. (East 5.4 software with ‘Null’ 
variance was used for total events and statistical significance boundary determination).  
 
A Kaplan-Meier plot of survival by arm will be created. Censored observations will be indicated 
on the Kaplan-Meier plot. Tabular summaries of the Kaplan-Meier analysis giving the median, 
quartiles, minimum and maximum will be displayed. 
 
The hazard ratio and its 95% confidence interval will be estimated using the Cox proportional 
hazard regression model with the same stratification factors as used in the log rank test. 
 
The following sensitivity analyses of the primary endpoint will be also performed using the 
ITT population: 
o Unstratified Log rank test and Cox model (No stratification and prognostic factors 
adjustment). 
o To analyze the effects of imbalance in the baseline characteristics and treatment 
with chemotherapy by adjusting for various covariates in the Cox proportional 
hazard regression model. In addition to treatment and the 3 stratification factors, 
the following prognostic factors16,33 will be included in the model simultaneously:  
Baseline PSA (values will be log transformed before inclusion, if any values = 0 
then all values will have 1 added before transformation to allow for all values to be 
included after transformation), baseline LDH (> ULN; ≥ ULN) (1/0), baseline 
ALP (values will be log transformed before inclusion), baseline albumin, baseline 
hemoglobin, Gleason score 2-7; 8-10) at initial diagnosis (1/0), opioid use (yes; 
no) (1/0), disease site (will be defined in a separate document). This will be done 
on the ITT population. 
 
Log transformation of covariates may be used in the model. The adjusted hazard ratio and its 
two-sided 95% confidence interval will be estimated using the Cox proportional hazard 
regression model with the covariates. 
 

 
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To assess the effect of the second line therapy on survival, the time from randomization to 
initiation of the first secondary therapy will be added as time-dependent covariate to the above 
primary Cox model. 
 
A separate summary of survival data will be provided for patients with leukapheresis or 
manufacturing failure. A sensitivity analysis including the real survival data of patients with 
leukapheresis or manufacturing failure as such (and not censored on Day 1), will be 
performed to show robustness of the primary analysis. Such sensitivity analysis is indeed 
more conservative and could potentially show lower treatment effect. It will be conducted 
with an intention to show that the results of the primary analysis are robust enough and their 
interpretability is not jeopardized. 
Additional exploratory analyses may be performed if deemed necessary. 
 
10.2.3 
 Supportive Analysis 
The primary endpoint OS will also be analyzed using the PP population to analyze sensitivity 
of the results to protocol deviations. Similar statistical methods as described for the primary 
analysis of OS will be used. The PP analyses for the primary efficacy endpoint will be used to 
support the primary analysis for OS using the ITT population. 
 
10.3 
Secondary Objectives 
 
10.3.1 
Secondary Efficacy Endpoints  
rPFS will be analyzed for both ITT and PP populations using similar statistical methods as 
described for the primary endpoint. Similarly, time to PSA progression, time to first skeletal 
related events and time to radiographic progression or SRE will be also analyzed. 
 
Incidence of skeletal related events (SRE) will be summarized. 
 
Definitions of endpoints reflect recommendations of PCWG229 (see section 7.3). For Soft tissue 
and Bone evaluations there will be Investigator based and IRF results. Both results to be 
recorded, but the IRF conclusion will be used for ultimate evaluation as specified in the trial 
specific Imaging Charter. Radiographic assessments by IRF will be considered as the primary 
analyses. 
  
A fixed sequential testing procedure will be used to test the 3 key secondary endpoints including 
rPFS, Time to PSA progression, and time to SRE. rPFS will be tested first. Then Hochberg7 
method will be used to test time to PSA progression and time to SRE in parallel. The details 
will be fully described in the SAP. 
 
No special data imputation algorithms will be used to replace missing data. 
 
For the analysis of OS, the last known date that the patient was alive will be used as the 
censoring date for those subjects that did not die at the time of analysis. As the period of 
treatment for any patient will be dependent on its efficacy and toxicity, the duration of follow-

 
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up will vary between subjects. Consequently, there will be no imputation for missing data. For 
time-to-event endpoints (e.g. time to rPFS, time to PSA progression and time to SRE), the last 
date of documented disease status will be used if event (progression) had not been documented 
at the time of the analysis or subjects had withdrawn the study prior to determination of 
progression; such subjects will be considered censored in the analysis. 
  
10.3.2 
Safety 
 
10.3.2.1 Adverse events 
AEs will be coded using MedDRA and grouped by System Organ Class. AE severity will be 
graded according to NCI CTCAE 4.03. An AE is considered treatment-emergent when the onset 
date of the event falls on or after the earliest start date of chemotherapy or study treatment and 
when the onset date of the event occurs until 30 days after the last dose given (first line chemo 
or study treatment) or when the AE worsens (increase in severity and/or frequency) on or after 
the earliest start date of chemotherapy or study treatment. Only treatment-emergent AEs 
occurring from the first dose through 30 days after the last dose of study treatment will be 
summarized.  
 
AEs will be classified according to severity and relationship to study medication. 
 
The number and percentage of subjects who experienced any treatment-emergent: AE, SAE, 
treatment related AE and treatment related SAEs, will be summarized. The denominator used 
to calculate incidence percentages consists of subjects in the Safety Population. Incidence of 
safety complications resulting from leukapheresis will also be reported in the analysis of safety.  
 
AEs will be grouped by System Organ Class and preferred term and sorted in descending 
frequency in the overall group. For tables by NCI CTCAE grade, if a patient has more than one 
AE the maximum grade will be summarized.  
 
Missing values will be treated as missing, except for causality of AEs to study drugs. If causality 
is missing, the AE will be regarded as related to study drug. 
 
10.3.2.2 Laboratory 
Clinical laboratory parameters will be used for individual patient safety monitoring. Laboratory 
values will be graded according to the NCI CTCAE 4.03. For each patient the baseline value is 
the value recorded at screening. The actual laboratory values and changes from baseline will be 
summarized by visit and by treatment. 
 
Laboratory abnormalities will be identified, summarized and presented in shift tables for each 
Study Cycle (baseline [Cycle 1, Day 1 pre-dose] versus Study Cycle toxicity grade) and by 
Worst Toxicity Grade (baseline versus worst toxicity grade across all visits). 
 

 
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10.3.2.3 Other safety data 
Physical examination findings will be captured at baseline and during the Treatment Period and 
abnormalities that represent a worsening or change from baseline will be reported as AEs. 
  
Vital signs will be summarized as measured values during the study and as change and 
percentage change from baseline to final visit. 
 
Body weight will be summarized as change and percentage changes from baseline to final visit. 
 
10.4 
Exploratory Endpoints 
 
10.4.1 
Quality of Life (QoL) 
Patient reported outcomes will include evaluation of QoL using the questionnaires FACT-P and 
EQ-5D (EQ-5D only in Europe). The QoL questionnaires FACT-P and EQ-5D will be 
summarized by treatment in accordance with the scoring manuals. Each score will be 
summarized by visit for the ITT population. Changes from baseline will be summarized and at 
specified time points of interest by treatment groups.  
 
Missing values related to patient reported outcomes will be treated in accordance with the 
appropriate scoring manual whenever possible. If it is not possible, the Last Observation Carried 
Forward (LOCF) imputation technique may be used. 
 
10.4.2 
Second Line Treatment 
Proportion of subjects requiring second line antineoplastic treatment introduction will be 
summarized. Time from randomization to second line treatment initiation will be described.  
 
10.5 
Pharmacokinetics 
Not applicable. 
 
10.6 
Immune Response Biomarkers and Gene Expressions 
See section 7.10 for description of these exploratory studies. 
 
10.7 
Sample Size Calculation 
Sample size (in terms of number of deaths) calculation assumptions:  
 
 A median survival of 24 months for the DCVAC/PCa group, 19 months for the control 
group and an exponential survival.7,8 
 
 Subjects were randomized into the study with 2:1 allocation ratio (i.e., DCVAC/PCa: 
placebo equal to 2:1). 
 
 Assume an exponential survival distribution, then hazard ratio can be calculated as 
HR = MR/MT, where MT and MR are the median survival times on test and reference, 
respectively, which results in HR = 0.792 in favor of the DCVAC/PCa group.  

 
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 Assuming proportional hazards  
 
 Two-tailed level of significance of 0.05 and 80% power, 
 
Based on the above assumptions, the sample size (in terms of number of deaths) would be 657 
events in total.  
 
To reach 657 events required, a total of 1170 patients will be enrolled in a 2:1 ratio (i.e., 
DCVAC/PCa vs. placebo equal to 2:1) with an expected enrollment period of approximately 18 
months, and total study duration of approximately 40 months to observe the required event-
driven timeframe of 657 total events for the final analysis. If the anticipated 657 events are not 
attained during the trial timeline, the study could be prolonged by SOTIO. 
 
Patients will be randomized in a 2:1 ratio, stratified by region (US vs Other), prior therapy 
(abiraterone or enzalutamide or neither of the two) and ECOG Score (0, 1 vs 2). 
 
The overall type I error rate will be controlled at 0.05.  
 
 

 
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11 
ADMINISTRATIVE PROCEDURES 
 
11.1 
Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance with the 
protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC and US Code of Federal 
Regulations Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
 
11.2 
Insurance 
Financial terms will be agreed upon in a separate contract document. 
For each participating patient the sponsor has taken out insurance covering the amount 
determined by respective national laws. All participating subjects will be informed about the 
existence of the insurance in detail in the patient informed consent. They have the right to 
review the terms and conditions described therein.  
 
11.3 
Responsibilities of the Investigator and IRB/IEC  
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) before study start. A 
signed and dated statement that the protocol and informed consent have been approved by the 
IRB/IEC must be given to SOTIO before study initiation. Prior to study start, the Investigator 
is required to sign a protocol signature page confirming his agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to SOTIO monitors, auditors, SOTIO 
Clinical Quality Assurance representatives, designated agents of SOTIO, IRBs/IECs and 
regulatory authorities as required. 
 
Where applicable by regulatory mandate all subjects participating in this clinical trial will 
receive from the investigator an alert card, which has been previously agreed by the sponsor 
and approved by the IRB/IEC, containing as minimum the name of the subject, the investigator 
contact number and information regarding the medical treatment received. 
 
Blood samples are being collected and stored for research purposes for this study. The sponsor 
of the trial, the tissue establishments/procurement organization, the manufacturer and the 
investigator institution should keep their parts of the traceability records for a minimum of 30 
years after the expiry date of the product, or longer if required by the terms of the clinical trial 
authorization or by the agreement with the sponsor. In the case of the tissue establishments, if 
that period is longer than provided in the Directives referred to in section 3, the sponsor should 
ensure through contractual agreements that the traceability records are kept for that longer 
period.  
 
11.4 
Informed Consent 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 

 
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so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his understanding. If the patient is capable of doing so, he 
should indicate assent by personally signing and dating the written informed consent document 
or a separate assent form. Informed consent must be obtained before conducting any study-
specific procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining informed consent should be documented in the patient source documents. 
 
SOTIO will provide to Investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
Investigator must be agreed to by SOTIO before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the SOTIO monitor after IRB/IEC approval. 
 
11.5 
Leukapheresis Procedure Informed Consent Form 
For the purpose of performing leukapheresis procedure apheresis center may ask patient to 
sign a separate not study specific consent form. 
 
11.6 
Amendments to the Protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by SOTIO, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC approval. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, SOTIO should 
be notified of this action and the IRB/IEC at the study site should be informed within 10 
working days. 
 
11.7 
Discontinuation of the Study 
SOTIO reserves the right to discontinue this study under the conditions specified in the clinical 
trial agreement. 
 
11.8 
Study Drug Supply and Re-supply, Storage and Tracking/Drug 
Accountability 
Study drugs must be received by a designated person at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the Investigator and designated 
assistants have access. Upon receipt, the DCVAC/PCa or placebo should be stored according 
to the instructions specified on the secondary package labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. 
 
Medication package labels will comply with the legal requirements of each country.  
 

 
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The Investigator must maintain an accurate record of the shipment and dispensing of study drug 
in a drug accountability ledger. Drug accountability will be noted by the field monitor during 
site visits and at the completion of the trial.  
 
At the conclusion of the study, and, as appropriate during the course of the study, the 
Investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to the monitor or to the SOTIO address provided in 
the Investigator folder at each site. 
 
 

 
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12 
PROTOCOL ADHERENCE 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact SOTIO or its agents, if any, monitoring the trial 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by SOTIO 
and approved by the IRB/IEC and concerned regulatory authorities, it cannot be implemented. 
All significant protocol deviations will be recorded and reported in the Clinical Study Report. 
 
 

 
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14 
APPENDICES 
 
14.1 
FACT-P Questionnaire 
 
Sample form and background available at: http://www.facit.org/FACITOrg/Questionnaires . 
For study purposes official forms will be distributed for completion by subjects. 
 
 

 
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CONFIDENTIAL 
Protocol No. SP005 
 
 
EudraCT: 2012-002814-38 
 
Oncology Clinical Trial Protocol  
(Version No.07.0, Final, 08Mar2018)  
Page 90 of 96 
 
 
 

 
CONFIDENTIAL 
Protocol No. SP005 
 
 
EudraCT: 2012-002814-38 
 
Oncology Clinical Trial Protocol  
(Version No.07.0, Final, 08Mar2018)  
Page 91 of 96 
 
 
 
 
 

 
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Protocol No. SP005 
 
 
EudraCT: 2012-002814-38 
 
Oncology Clinical Trial Protocol  
(Version No.07.0, Final, 08Mar2018)  
Page 92 of 96 
 
14.2 
EQ-5D Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
Protocol No. SP005 
 
 
EudraCT: 2012-002814-38 
 
Oncology Clinical Trial Protocol  
(Version No.07.0, Final, 08Mar2018)  
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Oncology Clinical Trial Protocol  
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Oncology Clinical Trial Protocol  
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14.3 
NCI CTCAE 
 
Version 4.03 of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE), dated 14 June 2010, may be viewed and/or downloaded by accessing the 
following website:  
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
  
14.4 
Protocol Violations/Deviations 
http://www.genome.gov/Pages/Research/Intramural/IRB/Deviation_Violation_examples8-07.pdf 
 
 
NIH IRB Professional Administrators Committee Version 5.1 
Regulatory Process Workgroup 1 11/18/2005 
 
Protocol Deviations and Violations 
Protocol Deviation- A protocol deviation is any change, divergence, or departure from the 
study design or procedures of a research protocol that is under the Investigator’s control and 
that has not been approved by the IRB. Upon discovery, the Principal Investigator is responsible 
for reporting protocol deviations to the IRB using the standard reporting form. Any change, 
divergence, or departure from the study design or procedures of a research protocol that affects 
the subject's rights, safety, or well-being and/or the completeness, accuracy and reliability of 
the study data constitutes a protocol violation. Changes or alterations in the conduct of the trial 
which do not have a major impact on the subject's rights, safety or well-being, or the 
completeness, accuracy and reliability of the study data are considered minor protocol 
deviations. 
 
Protocol Violation- A protocol violation is a deviation from the IRB approved protocol that 
may affect the subject's rights, safety, or well-being and/or the completeness, accuracy and 
reliability of the study data. If the deviation meets any of the following criteria, it is considered 
a protocol violation. 
 
Example list is not exhaustive. 
I. The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject. 
Examples: 
• A research subject received the wrong treatment or incorrect dose. 
• A research subject met withdrawal criteria during the study but was not withdrawn. 
• A research subject received an excluded concomitant medication. 
 
 
II. The deviation compromises the scientific integrity of the data collected for the study. 
Examples: 
• A research subject was enrolled but does not meet the protocol's eligibility criteria. 

 
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• Failure to treat research subjects per protocol procedures that specifically relate to primary 
efficacy outcomes. (if it involves patient safety it meets the first category above) 
• Changing the protocol without prior IRB approval. 
• Inadvertent loss of samples or data. 
NIH IRB Professional Administrators Committee Version 5.1 
Regulatory Process Workgroup 2 11/18/2005 
 
III. The deviation is a willful or knowing breach of human subject protection regulations, 
policies, or procedures on the part of the Investigator(s). 
Examples: 
• Failure to obtain informed consent prior to initiation of study-related procedures 
• Falsifying research or medical records. 
• Performing tests or procedures beyond the individual's professional scope or privilege status 
(credentialing) 
 
IV. The deviation involves a serious or continuing noncompliance with federal, state, local 
or institutional human subject protection regulations, policies, or procedures. 
Examples: 
• Working under an expired professional license or certification 
• Failure to follow federal and/or local regulations, and intramural research or CC policies 
• Repeated minor deviations. 
 
V. The deviation is inconsistent with the NIH Human Research Protection Program’s 
research, medical, and ethical principles. 
Examples: 
• A breach of confidentiality. 
• Inadequate or improper informed consent procedure. 
 
Minor Protocol Deviation- A minor protocol deviation is any change, divergence, or departure 
from the study design or procedures of a research protocol that has not been approved by the 
IRB and which DOES NOT have a major impact on the subject's rights, safety or well-being, 
or the completeness, accuracy and reliability of the study data.