Clinical trial NCT03002220
Conditions: Prostate Cancer
Sponsor: MedSIR
Start date: 2016-12-21; Completion date: 2021-06-09
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Radium-223 is indicated for the treatment of patients with mCRPC with symptomatic bone metastases and no known visceral metastatic disease. However, very few data have been reported in patients with mCRPC who are asymptomatic or mildly symptomatic. Recently, results from an International Expanded Access Program have also suggested a benefit of radium-223 in asymptomatic patients with mCRPC. In addition, the mechanism of action of radium-223 should not be correlated with the presence/absence of the AR-V7 mutation, although this issue has not yet been evaluated.

The aim of this study is to assess the efficacy of radium-223 in asymptomatic patients with mCRPC, and to establish the association between AR-V7 status and radium-223 activity.

Detailed description:
Primary objective:

To assess the efficacy of radium-223 in asymptomatic patients with mCRPC who have progressed while on abiraterone acetate or enzalutamide treatment.

Primary endpoint:

To determine the efficacy of radium-223 in terms of radiological rPFS.

Secondary objectives:

* Safety profile.
* To determine the association between AR-V7 status (positive vs. negative) and PFS.
* To establish the relationship between CTCs number with radium-223 efficacy.

Secondary endpoints:

Safety AEs will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) of the US National Cancer Institute (NCI) version 4.0 \[20\]. Grade 3 or 4 AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of the various combinations of drugs.

Efficacy

* Radiographic progression-free survival (rPFS) depending on AR-V7 status.
* Overall survival (OS).
* Time to first symptomatic skeletal event (SSE).
* Time to prostate specific antigen (PSA) progression according to the Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) study criteria.
* Determination percentage of PSA progression.
* Alkaline phosphatase level response (AF), normalization of alkaline phosphatase level, according to the ALSYMPCA study criteria.

Molecular aspects

* Assessment of AR-V7 mutation evolution during the study treatment.
* Determination changes in CTCs number during the study treatment.

Arms: arm 1: Patient will be treated with radium-223 at a dose of 55 kilobecquerel (kBq) (after 2015 National Institute of Standards and Technology's (NIST) implementation) per kilogram body weight, given at four-week intervals for six intravenous injections.
Interventions: intervention 1: radium-223
Intervention descriptions: intervention 1: Radium-223 at a dose of 55 kBq

Protocol documents:
Prot_000.pdf: 
 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
1 of 67 
 
Clinical Study Protocol 
 
 
A phase II clinical trial of radium-223 activity in patients with metastatic 
castration-resistant prostate cancer (mCRPC) with asymptomaticprogression 
while on abiraterone acetate or enzalutamide besides AR-V7 mutational status 
 
 
 
Protocol number: MedOPP098 
 
 
Study drug(s):  
 
Xofigo® 
 
 
 
 
 
EudraCT#: 
 
 
2016-001888-36 
No. in ClinicalTrials.gov:  
NCT03002220 
Protocol No.:  
 
MedOPP098 
 
 
Protocol date:  
 
30th January 2020 
 
 
Protocol Review History 
Initial Approval Version:  29th July 2016 
Amendment no. 1 
20th December 2016 
Amendment no. 2 
26th November 2018 
Amendment no. 3 
30th January 2020 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
2 of 67 
 
SPONSOR’S SIGNATURE PAGE 
 
 
Study title:A phase II clinical trial of radium-223 activity in patients with metastatic 
castration-resistant prostate cancer (mCRPC) with asymptomatic progression 
while on abiraterone acetate or enzalutamide besides AR-V7 mutational status. 
 
Study code: MedOPP098 
 
Version number and date: 4, dated on 30th January 2020 
 
 
 
 
 
 
Sponsor  
 
Signature 
 Signature date 
 (DD-Mmm-YYYY) 
 
 
 
Scientific Global Coordinator 
 
 
Signature 
 Signature date 
 (DD-Mmm-YYYY) 
 
 
 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
3 of 67 
 
KEY CONTACT DETAILS 
Sponsor  
Name:  
 
Medica Scientia Innovation Research S.L (MedSIR) 
Contact person:  
Lourdes Gómez 
Address: 
 
Torre Glòries, Av. Diagonal, 211, Planta 27, 08018-Barcelona, Spain 
Phone:  
 
+ 34 93 221 41 35 
Fax: 
 
 
+ 34 93 299 23 82 
E-mail:  
 
lourdes.gomez@medsir.org 
Scientific Global Coordinator 
Name:  
 
Joan Carles Galcerán 
Address: 
Paseo de la Vall d´Hebrón, 119-129, 08035-Barcelona, Spain 
E-mail:  
 
jcarles@vhio.net 
 
Medical Scientist 
Name: Javier Garde 
 
 
Address: Torre Glòries, Av. Diagonal, 211, Planta 27, 08018-Barcelona, Spain 
 
E-mail: javier.garde@medsir.org 
 
Reference Central Laboratory 
Name: Epic Sience 
 
 
 
Contact person: Megan Kearney 
Address: Covance Central Laboratory Services SARL, CENTERLINX Rue Moises-Marcinhes 7 
1217 Meyrin, Switzerland 
E-mail: megan.kearney@epicsciences.com 
 
 
 
Organizaciones de investigación por contrato 
Nombre: 
 
Experior S.L. 
Persona de contacto: 
Jaime A. Ballester 
Dirección:  
 
C/ Vicent Galmés, 1A 
 
 
 
46139 La Pobla de Farnals (València) 
Correo electrónico:  
ballester.jaime@experior.es 
 
Principal investigators 
Detailed in Appendix 4. 
 
 
 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
4 of 67 
 
Declaration of Investigators 
Protocol Title: A phase II clinical trial of radium-223 activity in patients with metastatic castration-resistant 
prostate cancer (mCRPC) with asymptomaticprogression while on abiraterone acetate or enzalutamide 
besides AR-V7 mutational status. 
 
Release date: 4, 30th January 2020 
Protocol number: MedOPP098 
I have received, reviewed and understood the following: 
 
a) 
Protocol: A phase II clinical trial of radium-223 activity in patients with metastatic 
castration-resistant prostate cancer (mCRPC) with asymptomatic progression while on 
abiraterone acetate or enzalutamide besides AR-V7 mutational status 
 
b) 
Summary of Product Characteristics containing clinical and non-clinical data on investigational 
product that are relevant to the study of the product on human subjects. 
I have been adequately informed as to the development to date of the investigational product. I will 
acknowledge receipt of the updated Summary of Product Characteristics. I have read this study protocol and 
agree that it contains all the information required to conduct the study. I agree to conduct this study as set 
out in this protocol. 
I understand that any change made by the investigator(s) not previously agreed to by the Sponsor may 
constitute a protocol non-compliance, including all of the ancillary studies or procedures performed on study 
patients (other than those procedures needed to ensure the patients’ well-being). I am aware that I can only 
deviate from or apply changes to the protocol without prior approval or the favorable opinion of the EC and/or 
before Sponsor approval to avoid immediate risk to the trial patients. Should this occur, I agree to inform the 
Sponsor as to the deviation or changes in writing and their reasons, as soon as possible. 
The study will be conducted in accordance with the moral, ethical, and scientific principles governing clinical 
research as set out in the Declaration of Helsinki and its amendments, the International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines (ICH E6 GCP) and applicable laws and 
regulations. 
I agree to receiving, as described in this protocol and in the ICH E6 guidelines forGCP, written informed 
consent from the patient or their legally authorized representative or the witnessed verbal informed consent 
from all patients who have been asked to participate in this study, before performing any study procedure. 
I will ensure that the study drug(s) provided by the Sponsor will only be used as described in this protocol. 
I am aware of the requirements for the correct reporting of serious adverse events, and I commit to document 
and to report such events as required by the Sponsor and in accordance with Health Authority Regulatory 
requirements. 
I agree to provide the Sponsor or Sponsor’s representative, upon request, with evidence of current laboratory 
accreditation, the name and address of the laboratory, and a list of normal values and ranges. 
I agree to the use of study results for national and international registration, publication, and information for 
medical and pharmaceutical professionals. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
5 of 67 
 
I agree to keep all source documents and case report forms as specified in the relevant sections of this 
protocol. 
I agree to submit all the forms required by the health authoritiesand my updated curriculum vitae and those 
of the sub-investigators and all of the members of my team (if applicable) before the start of this study, which 
may be submitted, in turn, to the Health Authorities. 
I am aware that the Sponsor or their representative may perform audits and that the Health Authorities may 
carry out inspections as part of the conduct of this study. I will permit monitoring, audit and inspection and 
provide direct access to source data, documents and reports for these purposes. 
In light of the foregoing, I hereby consent to the inclusion by the Sponsor of my contact details and 
professional profile in their electronic database to be used for internal purposes and for submission to Health 
Authorities worldwide. 
 
Name:   
_____________________________________________________________________ 
Signature:  
_________________________ 
 
Date:  
___________________________ 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
6 of 67 
 
Protocol synopsis 
Investigational drug: 
Xofigo® 
Protocol number: 
MedOPP098 
Eudract Number: 
2016-001888-36 
Protocol Title: 
A phase II clinical trial of radium-223 activity in patients with 
metastatic castration-resistant prostate cancer (mCRPC) with 
asymptomatic progression while on abiraterone acetate or 
enzalutamide besides androgen receptor (AR)-V7 mutational status.  
Study disease: 
Patients with mCRPC with asymptomatic progression while on 
abiraterone 
acetate 
or 
enzalutamide.The 
progression 
on 
enzalutamide or abiraterone acetate will be defined as patients who 
confirm radiographic progression and/or prostate-specific antigen 
(PSA) progression with rapid PSA doubling time (less than three 
months). 
Patients: 
Patients ≥ 18 years of age diagnosed with mCRPC with bone 
metastases and asymptomaticprogression after at least 24 weeks of 
treatment with abiraterone acetate or enzalutamide. 
Number of patients: 
52 patients  
Screening criteria: 
Inclusion criteria 
• 
Subject is an adult ≥ 18 years at the time of informed consent and 
has signed informed consent before any trial related activities and 
according to local guidelines. 
• 
Subject has histologically confirmed adenocarcinoma of the 
prostate without neuroendocrine differentiation or small cell 
features. 
• 
Subject has bone metastases due to the prostate cancer and 
absence of visceral metastases. 
• 
Subject has a serum testosterone of ≤ 1.7 nmol/L (or ≤ 50 ng/dL) 
at screening. 
• 
Subject must have received a minimum of 24 weeks of treatment 
with abiraterone acetate or enzalutamide within its approved label 
indication and has discontinued use at least four weeks prior to 
start of study drug at day 1. 
• 
Prior use of docetaxel is allowed in castration-naïve patients 
(maximum of six cycles). 
• 
Subject receives and will continue to receive ongoing androgen 
deprivation with luteinizing releasing hormone (LHRH) analogue 
therapy throughout the course of the study or has had a bilateral 
orchiectomy. 
• 
Subject is asymptomaticfrom prostate cancer, defined as patients 
with the score on brief pain inventory (short form) (BPI-SF) 
Question #3 must be zero or one and no use of opiate analgesics 
for prostate cancer-related pain currently or anytime within two 
weeks prior to screening. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
7 of 67 
 
• 
Subject has an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0–1 at screening. 
• 
Subject receiving bisphosphonate or other approved bone-
targeting therapy must have been on stable doses for at least four 
weeks prior to start of study drug at day 1. 
• 
Subject has a life expectancy of more than or equal to 12 months. 
• 
Subject agrees not to participate in another interventional study 
while on study drug. 
• 
Subject and his female partner who is of childbearing potential 
must use two acceptable methods of birth control (one of which 
must include a condom as a barrier method of contraception) 
starting at screening and continuing throughout the study period 
and for six months after final study drug administration. 
 
Exclusion criteria 
Any patient meeting ANY of the following criteria will be excluded from 
the study: 
• 
Subject has received any anti-neoplastic therapy (including 
ketokonazol and chemotherapy) following abiraterone acetate or 
enzalutamide discontinuation and prior to start of study drug at 
day 1. 
• 
Subject has known or suspected brain metastases or active 
leptomeningeal disease. 
• 
Subject has concurrent disease or any clinically significant 
abnormality following the investigator’s review of the physical 
examination and safety laboratory tests at screening, which in the 
judgment of the investigator would interfere with the subject's 
participation in this study or evaluation of study results. 
• 
Subject has a history of another invasive cancer within three 
years prior to screening, with the exceptions of non-melanoma 
skin cancers or a non-infiltrating muscle bladder cancer that have 
a remote probability of recurrence in the opinion of the 
investigator in consultation with the medical scientist. 
• 
Subject had major surgery within one month prior to screening. 
• 
Subject has received investigational therapy within 28 days or 5 
half lives, whichever is longer, prior to start of study drug at day 
1. 
• 
Subject has absolute neutrophil count < 1,500/μL, platelet count 
< 100,000/μL, and hemoglobin < 6.25 mmol/L (or < 10 g/dL) at 
screening (Note: Subjects must not have received any growth 
factors or blood transfusions within seven days of the hematologic 
laboratory values obtained at screening). 
• 
Subject has total bilirubin > 1.5 times the upper limit of normal 
(ULN) at screening, except for subjects with documented Gilbert’s 
syndrome. 
• 
Subject has creatinine > 2.5 mg/dL at screening. 
• 
Subject has albumin ≤ 30 g/L (or ≤ 3.0 g/dL) at screening. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
8 of 67 
 
Study objectives 
Primary objective:  
To assess the efficacy of radium-223 in asymptomaticpatients with 
mCRPC who have progressed while on abiraterone acetate or 
enzalutamide treatment. 
Secondary objectives: 
• 
Safety profile. 
• 
To determine the association between AR-V7 status (positive vs. 
negative) and progression-free survival (PFS). 
• 
To establish the relationship between circulating tumor cells 
(CTCs) numberwith radium-223 efficacy. 
Type of study: 
Multicenter, single-arm, open-label, non-controlled phase IIa clinical 
trial.  
Study Treatment: 
Once the informed consent has been signed and the study screening 
criteria have been confirmed, the patient will be treated with radium-
223 at a dose of 55 kBq (after 2015 NIST implementation) per 
kilogram body weight, given at four-week intervals for sixintravenous 
injections.Adjustment of dose level is not permitted. 
Patients will receive study treatment according to the protocol and will 
be prematurely discontinued in the following situations: disease 
progression, occurrence of unacceptable side effects, death, or 
withdrawal of consent, whichever occurs first. 
Patients who complete the study treatment during its active treatment 
phase will enter a follow-up period, with radiological tumor 
assessment every three months (±7 working days) until disease 
progression and safety evaluation to follow-up of symptomatic 
skeletal related events until reach 2 years from the last dose of study 
treatment. If patient discontinued treatment for any reason other than 
progression, tumor reevaluation will be included in the assessment. 
After disease progression, a safety follow-up visit will be performed 
within three following months (including survival status and post-study 
anticancer therapy evaluation) and 2 years after last dose of study 
drug. Safety evaluation after progression will include follow-up of 
symptomatic skeletal related events and overall survival. 
 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
9 of 67 
 
Safety and efficacy 
assessments 
Efficacy assessments:  
Assessments (CT scan and bone scan) will be performed from the 
time of enrollment (baseline assessments) and every 12 weeks 
(± 7 working days) from the time of the first administered dose. 
Radiographic disease progression will be assessed using The 
Prostate Cancer Clinical Trials Working Group (PCWG2) modified 
criteria for bone disease and the Response Evaluation Criteria in Solid 
Tumors (RECIST criteria) version 1.1 for soft-tissue disease. 
Radiographic disease progression in bone will require persistence of 
new lesions on a confirmatory bone scan performed at least six weeks 
later. It is highly recommended to perform additional CT scans and 
bone scans if clinical progression disease is suspected.  
During the active phase of the study treatment, each assessment will 
be performed in accordance with the schedule (Appendix 1: Schedule 
of study assessments and procedures), regardless of any delay in 
administration, to prevent bias in the efficacy assessment. If any of 
the required assessments are not performed, the disease status at 
that point in time will not be known. 
Safety assessments:  
The occurrence and maximum grade of side effects observed 
throughout the study will be listed and tabulated according to type and 
dose level. Any adverse events (AEs) that the investigator reports as 
unrelated to the drug will also be reported. In this study, side effects 
will be assessed according to the US National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0. 
Other assessments: 
To perform the molecular analyses described in this protocol 
(Appendix 3: Instructions for blood sample collection. Detection of 
CTCs), patients will be asked to give their consent to the collection of 
the following biological material: 
- Blood samples: These will be collected at the start of the study, at 
the end of treatmentand when documenting disease progression for 
the purpose of CTC. 
Endpoints 
Primary endpoint: 
The primary endpoint of this study is to assess the efficacy of radium-
223 in terms of radiological rPFS. 
Secondary endpoints: 
Safety 
AEs will be evaluated using the NCI-CTCAE version 4.0. Grade 3 or 
4 AEs and serious adverse events (SAEs) will be assessed to 
determine the safety and tolerability of the various combinations of 
drugs. 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
10 of 67 
 
Efficacy 
• 
Radiographic progression-free survival (rPFS) depending on 
AR-V7 status. 
• 
Overall survival (OS). 
• 
Time to first symptomatic skeletal event (SSE). 
• 
Time to PSA progresionaccording to the ALSYMPCA study 
criteria. 
• 
Determination percentage of PSA progresion. 
• 
Alkaline phosphatase level response (AF), normalization of 
alkaline phosphatase level, according to the ALSYMPCA 
study criteria. 
 
Molecular aspects 
• 
Assessment of AR-V7 mutation evolution during the study 
treatment. 
• 
Determination changes in CTCs number during the study 
treatment. 
Study calendar 
Start Recruitment (FPI):  
 
Nov-2016 
End of Recruitment (LPI):  
 
Oct-2018 
Follow-up period for efficacy: 
             Nov-2019 
Follow-up extension for safety:              Apr-2021 
Final efficacy report:  
 
 
Sept-2020 
 
Final safety report: 
 
 
Aug-2021 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
11 of 67 
 
List of abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AF 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AR 
Androgen Receptor 
AR-FL 
Full-Length-Androgen Receptor 
AR-V7 
Androgen Receptor Splice Variant-7  
AST 
Aspartate transaminase 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Cytokeratin 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRPC 
Castration-Resistant Prostate Cancer 
CT 
Computerized Axial Tomography 
CTC 
Circulating Tumor Cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
DK 
DecayCorrection Factor 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicine Agency 
EoS 
End of Study 
ESA 
Erythropoietin Stimulating Agents 
FDA 
US Food and Drug Administration 
FL 
Full-Length 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GMP 
Good Manufacturing Practice 
HD 
High Definition 
HR 
Hazard Ratio 
HRQOL 
Health-Related Quality Of Life 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IMP 
Investigational Medicine Product 
IV 
Intravenous 
LHRH 
Luteinizing Releasing Hormone 
LPLV 
LastPatient Last Visit 
mCRPC 
Metastatic Castration-Resistant Prostate Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
Non-IMP 
Non-Investigational Medicinal Product 
OR 
Odds Ratio 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
12 of 67 
 
Abbreviation 
Definition 
OS 
Overall Survival 
PCWG 
Prostate Cancer Clinical Trials Working Group 
PFS 
Progression-Free Survival 
PSA 
Prostate-Specific Antigen 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic Acid 
RR 
Relative Risk 
RT-PCR 
Reverse-Transcription Polymerase-Chain-Reaction  
SAE 
Serious Adverse Event 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SRE 
Skeletal-Related Event 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
UPN 
Unique Patient Number 
WBC 
White Blood Cell 
 
 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
13 of 67 
 
 
Table of contents 
 
KEY CONTACT DETAILS ............................................................................................................ 3 
Protocol synopsis ....................................................................................................................... 6 
1. 
STUDY BACKGROUND AND RATIONALE .............................................................. 16 
1.1. 
State-of-the-art treatment of metastatic castration-resistant prostate cancer 
(mCRPC) ..................................................................................................................... 16 
1.2. 
The role of radium-223 in patients with mCRPC ......................................................... 18 
1.3. 
AR mutations as a driver of therapeutic resistance in mCRPC ................................... 19 
1.4. 
Study rationale ............................................................................................................. 20 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 21 
2.1. 
Primary objective ......................................................................................................... 21 
2.2. 
Secondary objectives .................................................................................................. 21 
3. 
STUDY OVERVIEW .................................................................................................... 21 
3.1. 
Type of study ............................................................................................................... 21 
3.2. 
Study schedule ............................................................................................................ 22 
3.3. 
General concomitant medication and additional assistance guidelines ...................... 23 
3.4. 
Prohibited therapies ..................................................................................................... 24 
3.5. 
Duration of study treatment (treatment phase) ............................................................ 24 
3.6. 
Duration of post-treatment follow-up period (follow-up phase) .................................... 24 
3.7. 
EoS .............................................................................................................................. 24 
4. 
PATIENT SCREENING ............................................................................................... 24 
4.1. 
Study population .......................................................................................................... 25 
4.2. 
Inclusion criteria ........................................................................................................... 25 
4.3. 
Exclusion criteria ......................................................................................................... 26 
5. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................... 26 
5.1. 
Screening phase: Patient enrollment procedures ........................................................ 26 
5.2. 
Treatment phase: Assessments .................................................................................. 28 
5.3. 
Follow-up phase .......................................................................................................... 31 
5.4. 
Assessment schedule .................................................................................................. 32 
5.5. 
Discontinuation of patient, study, or site participation ................................................. 32 
6. 
STUDY DRUG INFORMATION .................................................................................. 33 
6.1. 
Study treatment ........................................................................................................... 33 
6.2. 
Drug supply ................................................................................................................. 33 
6.3. 
Dosage and administration .......................................................................................... 34 
6.4. 
Dose calibration ........................................................................................................... 34 
6.5. 
Dose handling .............................................................................................................. 35 
6.6. 
Dose calculation .......................................................................................................... 35 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
14 of 67 
 
6.7. 
Dose preparation ......................................................................................................... 36 
6.8. 
Dose administration ..................................................................................................... 36 
6.9. 
Medication errors and overdose .................................................................................. 36 
6.10. 
Treatment compliance ................................................................................................. 37 
6.11. 
Dose adjustments ........................................................................................................ 37 
6.12. 
Possible drug interactions ........................................................................................... 38 
7. 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ................................. 38 
7.1. 
Definitions of AEs ........................................................................................................ 39 
7.2. 
Reporting of AEs ......................................................................................................... 41 
7.3. 
Safety reporting flow chart ........................................................................................... 43 
8. 
STATISTICAL CONSIDERATIONS AND STATISTICAL ANALYSIS PLAN ............ 46 
8.1. 
Determination of sample size ...................................................................................... 46 
A total of 52 patients will be enrolled into this trial. We expect that the most of patients 
will be AR-V7-negative (46 patients) and 6 patients will be AR-V7-positive. ............... 46 
8.2. 
Justification of sample size .......................................................................................... 46 
8.3. 
Statistical plan ............................................................................................................. 47 
Unless otherwise mentioned all tests will be two-sided. .......................................................... 47 
8.3.1. 
Primary efficacy endpoint ...................................................................................... 47 
8.3.2. 
Secondary endpoints ............................................................................................. 49 
8.3.3. 
Analysis sets .......................................................................................................... 50 
8.3.4. 
Analysis of baseline and demographic variables ................................................... 50 
8.3.5. 
Efficacy analysis .................................................................................................... 50 
8.3.6. 
Decision rules and adjustment of alpha for primary endpoint ................................ 50 
8.4. 
Efficacy results ............................................................................................................ 50 
8.5. 
Safety results ............................................................................................................... 51 
8.6. 
Missing data management .......................................................................................... 51 
8.7. 
Scientific committee review ......................................................................................... 52 
9. 
ETHICAL CONSIDERATIONS ................................................................................... 53 
9.1. 
Regulatory and ethical compliance .............................................................................. 53 
9.2. 
EC ................................................................................................................................ 53 
9.3. 
Informed consent ......................................................................................................... 53 
9.4. 
Data protection ............................................................................................................ 54 
10. 
ORIGINAL DOCUMENTS, STUDY MONITORING AND QUALITY ASSURANCE ... 54 
10.1. 
Source data record ...................................................................................................... 54 
10.2. 
Study monitoring and source data verification ............................................................. 55 
10.3. 
Record retention .......................................................................................................... 56 
10.4. 
Data quality assurance ................................................................................................ 56 
11. 
DATA MANAGEMENT ............................................................................................... 57 
11.1. 
Data entry and processing ........................................................................................... 57 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
15 of 67 
 
11.2. 
Data clarification .......................................................................................................... 57 
11.3. 
Data coding procedures .............................................................................................. 57 
12. 
STUDY MANAGEMENT ............................................................................................. 57 
12.1. 
Study discontinuation .................................................................................................. 57 
12.2. 
Protocol amendments .................................................................................................. 57 
12.3. 
Publication policy and protection of trade secrets ....................................................... 58 
12.4. 
Insurance ..................................................................................................................... 58 
13. 
REFERENCES ............................................................................................................ 59 
Appendix 1: Schedule of study assessments and procedures ............................................ 61 
Appendix 2: Response Evaluation Criteria in Solid Tumors Guidelines (RECIST criteria) 
(version 1.1) ............................................................................................................................... 65 
Appendix 3: Instructions for serum/plasma sample collection. Detection of CTCs ........... 65 
Appendix 4: Principal investigators ........................................................................................ 67 
 
 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
16 of 67 
 
1. STUDY BACKGROUND AND RATIONALE 
 
1.1. State-of-the-art treatment of metastatic castration-resistant prostate cancer (mCRPC) 
 
Prostate canceristhe most frequent urogenital malignancy, the most common solid neoplasm, and 
the second most common cause of cancer death in men in Europe [1]. In 2015, an estimated 
222,800 new cases of prostate cancer will be diagnosed in the United States, and around 27,000 
patients died from prostate cancer .  
When there is a suspicion that prostatecancer is present based on the digital rectal exam, 
prostate-specific antigen (PSA) level, and radiological findings, a prostate biopsy must be 
performed cover with transrectal ultrasound guidance, and a minimum of eight cores must be 
obtained. The pathology report should include a description of the cells, the cancer grading 
(Gleason score), and the final pathologist's diagnosis.  
Clinically localised prostate cancer should be categorised as low-, intermediate-, or high-risk using 
a classification that incorporatesGleason score, PSA level, and clinical stage. There is no 
consensus regarding optimum management of localised disease. Options include watchful 
waiting, active surveillance, open, laparoscopic or robotic-assisted radical prostatectomy, external 
beam radiotherapy, and brachytherapy[2].  
After radical local therapy, about 30% of patients will develop advanced disease. Androgen-
suppressing strategies have become the mainstay treatment of advanced prostate cancer. 
Androgen suppression using bilateral orchiectomy or an luteinizing releasing hormone(LHRH) 
agonist/antagonist should be first-line treatment. Furthermore, complete or maximal androgen 
blockade with the addition of an antiandrogen has been associated with a small five-year survival 
advantage, of less than 5% [3]. However, more recent results from the CHAARTED study showed 
an increase in overall survival (OS) in patients with hormone-sensitive prostate cancer treated 
with continuous androgen deprivation therapy in association with six cycles of docetaxel-based 
chemotherapy compared with androgen deprivation therapy alone (median, 57.6 vs. 44 months; 
hazard ratio (HR), 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001)[4]This difference 
was even higher among patients with high-volume disease(median, 49.2 vs. 39.2 months; HR, 
0.60; 95% CI, 0.45 to 0.81;  P<0.001). These results contrast with those of the GETUG-AFU 15 
trial, performed in a similar population, in which no OS differences were found [5]. 
Castration-resistant prostate cancer (CRPC) is defined as cancer progression in the setting of 
“castrate levels” of serum androgens (generally ≤50 ng/dL). However, a number of patients with 
castrate-resistant disease will continue to respond to secondary hormonal manipulations such as 
other antiandrogens, estrogen agonists, corticosteroids, and steroidogenesis inhibitors. 
Enzalutamide (MDV3100) attacks multiple nodes in the androgen receptor (AR) signaling 
pathway. It is a competitive inhibitor of AR ligand binding, with greater affinity for the AR and 
superior potency than other antiandrogens. Additionally, enzalutamide prevents nuclear 
translocation of the AR, and induces a conformational change that inhibits the receptor-complex 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
17 of 67 
 
binding to androgen-response elements of deoxyribonucleic acid (DNA), thereby preventing 
activation of target genes necessary for prostate cancer growth. 
Enzalutamide was initially approved for the treatment of patients with mCRPC who have 
previously received docetaxel. The approval was based on the results of the AFFIRM study, a 
phase III randomized placebo-controlled multicenter trial that enrolled 1,199 patients with mCRPC 
who had received prior docetaxel[6]. Patients were randomly assigned, in a 2:1 ratio, to receive 
enzalutamide 160 mg orally once daily (N = 800) or placebo (N = 399). The primary 
efficacyendpoint was OS. At the pre-specified interim analysis after 520 events, a statistically 
significant improvement in OS was observed in enzalutamide-treated patients compared with 
patients in the placebo group (median, 18.4 vs. 13.6 months; HR, 0.63; 95% CI, 0.53 to 0.75; 
P<0.0001).Enzalutamide is generally very well tolerated. There were very few toxicities that were 
more common in the enzalutamide arm, and these included fatigue, diarrhea, musculoskeletal 
pain, headache, hypertension, and hot flashes. 
Subsequently, enzalutamide was also approved for the treatment of patients with mCRPC who 
are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom 
chemotherapy is not yet clinically indicated. This indication was based on the results of the 
PREVAIL study, a phase III randomized placebo-controlled multicenter trial that enrolled 1,717 
patients with mCRPC who had not received prior docetaxel[7]. Patients were randomly assigned, 
in a 1:1 ratio, to receive enzalutamide 160 mg orally once daily (N = 872) or placebo (N = 845). 
Coprimary endpoints were radiographic progression-free survival (PFS) and OS. At the planned 
interim analysis after 440 events, a statistically significant improvement in OS was observed in 
enzalutamide-treated patients compared with patients in the placebo group (median, 32.4 vs. 30.2 
months; HR, 0.71; 95% CI, 0.60 to 0.84; P<0.001). 
Abiraterone acetate, a prodrug of abiraterone, is a selective inhibitor of androgen biosynthesis 
that potently blocks cytochrome P450 c17 (CYP17), an essential enzyme in testosterone 
synthesis, thereby inhibiting androgen synthesis by the adrenal glands and testes and within the 
prostate tumor.  
Like enzalutamide, abiraterone acetate was initially approved in combination with prednisone to 
treat patients with mCRPC who have received prior docetaxel. The approval was based on the 
results of the COU-AA-301 study, a phase III randomized placebo-controlled multicenter trial that 
enrolled 1,195 patients with mCRPC who had received prior docetaxel [8]. Patients were 
randomly assigned, in a 2:1 ratio, to receive abiraterone acetate 1000 mg orally once dailyplus 
prednisone 5 mg orally twice daily (N = 797) or placebo plus prednisone (N = 398). The primary 
efficacyendpoint was OS. At the pre-specified interim analysis after 552 events, a statistically 
significant improvement in OS was observed in abiraterone-treated patients compared with 
patients in the placebo group (median, 14.8 vs. 10.9 months; HR0.66; 95% CI, 0.55 to 0.78; 
P<0.001). Although the most common adverseeffect (AE)was fatigue,AEs associated with 
elevated mineralocorticoid levels due to CYP17 blockade (fluid retention and edema, 
hypokalemia, and hypertension), as well as cardiac disorders and liver-function test 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
18 of 67 
 
abnormalities, were also more common in the abiraterone-treated patients (55% vs. 43%, 
P<0.001). 
Subsequently, abiraterone acetate was also approved for the treatment patients with mCRPC 
who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in 
whom chemotherapy is not yet clinically indicated. This indication was based on the results of the 
COU-AA-302 study, a phase III randomized placebo-controlled multicenter trial that enrolled 
1,088 patients with mCRPC who had not received prior docetaxel[9]. Patients were randomly 
assigned, in a 1:1 ratio, to receive abiraterone acetate 1000 mg orally once dailyplus prednisone 
5 mg orally twice daily (N = 546) or placebo plus prednisone (N = 542). Coprimary endpoints were 
radiographic PFSand OS. At the planned interim analysis after 333 events, a statistically 
significant improvement in OS was observed in abiraterone-treated patients compared with 
patients in the placebo group (median, not reached vs. 27.2 months; HR, 0.75; 95% CI, 0.61 to 
0.93; P=0.01). 
Therefore, several agents have become available for the treatment of patients with mCRPC. 
Front-line therapeutic options for mCRPC include docetaxel, sipuleucel-T[10], abiraterone 
acetate, enzalutamide, and radium-223. Post-docetaxel options include cabazitaxel[11], 
abiraterone acetate, enzalutamide, and radium-223. However, it is unclear what the optimal 
sequencing of these therapies should be in order to maximize clinical outcomes and survival. The 
results of a preliminary study have suggested that the sequence of abiraterone acetate followed 
by enzalutamide may produce clinically superior outcomes in patients with mCRPC compared 
with enzalutamide followed by abiraterone acetate[12]. To address this issue, a prospective phase 
II clinical trial is currently under way (NCT02125357). Investigators will randomize patients with 
mCRPC to receive either first-line abiraterone acetate or enzalutamide, and patients will 
subsequently cross over to the alternative agent at the time of PSA progression.  
 
1.2. The role of radium-223 in patients with mCRPC 
Radium-223 (molecular formula 223RaCl2)is an alpha-emitting radioisotope that targets areas of 
bone with hight turnover asmetastasis and is excreted by the small intestine. When compared 
with beta-emitters, radium-223 delivers a high quantity of energy per track length with short tissue 
penetration. 
After injection radium-223 is rapidly cleared from the blood and distributed to bone and intestine. 
Radium-223 has a physical half-life of 11.43 days and approximately 63% of the administered 
radioactivity is excreted from the body within seven days, primarily via the fecal route. Dosimetry 
data suggest that bone, bone marrow, and the intestinal wall have the highest absorbed radiation 
doses [13]. 
Thesafetyand tolerability of radium-223 was initially evaluated in a single injection dose ranging 
study in 25subjects diagnosed with prostate (N = 15) or breast cancer (N = 10)[14]. Five subjects 
were included at each of the doses: 46, 93, 163, 213, or 250 kBqper kilogram body weightand 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
19 of 67 
 
followed for eight weeks. In this study, radium-223 presented a dose-proportional increase in 
exposure with mild and reversible myelosuppression. Preliminaryevidence of efficacywas 
observed with reduction in serum alkaline phosphatase (AF) levels and improved pain control 
across the dose levels.Radium-223 was subsequently evaluated in a double-blind, placebo-
controlled, multicenter randomized phase II study.Patients diagnosed with mCRPCand bone pain 
were randomly assigned, in a 1:1 ratio, to receiveexternal beam radiotherapy and radium-223 50 
kBq per kilogram body weight (N = 33), given at four-week intervals for four injections, or external 
beam radiotherapy and placebo (N = 31)[15].External beam radiation therapy was administered 
at the most painful site in each subject. The primary efficacyendpoints were the activity of radium-
223 treatment with respect to the reduction in bone-specific AF levels and time to occurrence of 
studydefined skeletal events (SSEs). There were no differences in the time to first SSE (median, 
14 vs. 11 weeks; 95% CI,9 to 30; P=0.257), although there was a statisticallysignificant reduction 
in the median of all serum markers forsubjects who received radium-223. 
Radium-223 (Xofigo®) is indicated for the treatment of patients with mCRPC with symptomatic 
bone metastases and no known visceral metastatic disease.In the pivotalphase IIIclinical trial (the 
ALSYMPCA study), a total of 921 subjectswith mCRPC with bone metastases were randomly 
assigned, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram 
of body weight intravenously) or matching placebo; one injection was administered every four 
weeks[16]. Prior to randomization, 58% and 57% of patients had received docetaxel in the radium-
223 and placebo arms, respectively. The median duration of treatment was 20 weeks (six cycles) 
for radium-223 and 18 weeks (five cycles) for placebo. Radium-223, as compared with placebo, 
significantly improved OS (median, 14.0 vs. 11.2 months; HR, 0.70; 95% CI, 0.55 to 0.88; 
P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit 
(median, 14.9  vs. 11.3 months; HR, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all 
main secondary efficacy endpoints also showed a benefit of radium-233 as compared with 
placebo. The most common AEs (≥ 10%) in patients receiving radium-223 were nausea (2% 
grade 3-4), diarrhea (2% grade 3-4), vomiting (2% grade 3-4), and peripheral edema (2% grade 
3-4). The most common hematologic laboratory abnormalities in radium-223-treated patients (≥ 
10%) were anemia (6% grade 3-4), lymphocytopenia (20% grade 3-4), leukopenia (3% grade 3-
4), thrombocytopenia (3% grade 3-4), and neutropenia (2% grade 3-4). Treatment 
discontinuations due to AEs occurred in 17% of patients who received radium-223 and 21% of 
patients who received placebo. 
1.3. AR mutations as a driver of therapeutic resistance in mCRPC 
The AR is a steroid receptor; a sub-family of receptors characterised as ligand dependent, 
sequence specific transcription factors, and like other nuclear receptors, the AR has a modular 
structure. The AR gene is situated at Xq11-12 and consists of 8 exons with exon 1 encoding the 
N-terminal domain and the entire 5’ untranslated region, exons 2 and 3 encoding the DNA binding 
domain (DBD), and exons 4-8 encoding the “hinge” region and ligand binding domain (LBD).The 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
20 of 67 
 
androgen induced transcriptional activation of AR is modulated by the interaction of AR with 
coregulators and by phosphorylation of AR and AR coregulators in response to growth factors[17]. 
AR and the modulators of AR activity remain important in prostate cancer. Approximately 80-90% 
of prostate cancers are dependent on androgen at initial diagnosis, and endocrine therapy of 
prostate cancer is directed toward the reduction of serum androgens and inhibition of AR. 
However, androgen ablation therapy ultimately fails, and prostate cancer progresses to a 
hormone refractory state.  
AR mutations have been extensively reported in patients with prostate cancer. In early stages of 
prostate cancer, mutations of the AR are rare, but their frequency is significantly increased in 
advanced androgen-independent tumors, suggesting that AR mutations play a role in tumor 
progression[18]. 
Recently, it has been published the clinical relevance of AR variants in mCRPC through the 
prospective evaluation of the AR splice variant 7 messenger ribonucleic acid(RNA) (AR-V7) in 
circulating tumor cells (CTCs) from patients receiving enzalutamide and abiraterone acetate [19]]. 
A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were included, of 
whom 39% and 19%, respectively, had detectable AR-V7 in CTCs. The overall proportion of 
patients who had a PSA response while receiving enzalutamide was 32% (95% CI, 17 to 51; 10 
of 31 men). However, the PSA response rate among AR-V7–positive patients was 0% (95% CI, 
0 to 26; 0 of 12 men), whereas the rate among AR-V7–negative patients was 53% (95% CI, 29 
to 76; 10 of 19 men; P=0.004). Regarding abiraterone-treated patients, the overall proportion of 
patients who had a PSA response while receiving abiraterone acetate was 55% (95% CI, 36 to 
73; 17 of 31 men). In the same way, the PSA response rate among AR-V7–positive patients was 
0% (95% CI, 0 to 46; 0 of 6 men), whereas the rate among AR-V7–negative patients was 68% 
(95% CI, 46 to 85; 17 of 25 men; P=0.004). The authors concluded that the detection of AR-V7 in 
CTCs from patients with mCRPC may be associated with resistance to enzalutamide and 
abiraterone acetate.  
1.4. Study rationale 
Radium-223 is indicated for the treatment of patients with mCRPC with symptomatic bone 
metastases and no known visceral metastatic disease. However, very few data have been 
reported in patients with mCRPC who are asymptomatic or mildly symptomatic. Recently, results 
from an International Expanded Access Program have also suggested a benefit of radium-223 in 
asymptomatic patients with mCRPC. In addition, the mechanism of action of radium-223 should 
not be correlated with the presence/absence of the AR-V7 mutation, although this issue has not 
yet been evaluated. 
The aim of this study is to assess the efficacy of radium-223 in asymptomatic patients with 
mCRPC,and to establish the association between AR-V7 status and radium-223 activity. 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
21 of 67 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Primary objective 
To assess the efficacy of radium-223 in asymptomatic patients with mCRPC who have 
progressed while on abiraterone acetate or enzalutamide treatment. 
Primary endpoint:  
To determine the efficacy of radium-223 in terms of radiological rPFS. 
2.2. Secondary objectives 
• 
Safety profile. 
• 
To determine the association between AR-V7 status (positive vs. negative) and PFS. 
• 
To establish the relationship between CTCs number with radium-223 efficacy. 
Secondary endpoints: 
Safety 
AEs will be evaluated using the Common Terminology Criteria for Adverse Events(CTCAE) of the 
US National Cancer Institute (NCI) version 4.0[20]. Grade 3 or 4 AEs and serious adverse events 
(SAEs) will be assessed to determine the safety and tolerability of the various combinations of 
drugs. 
 
Efficacy 
• 
Radiographic progression-free survival (rPFS) depending on AR-V7 status. 
• 
Overall survival (OS). 
• 
Time to first symptomatic skeletal event (SSE). 
• 
Time to PSA progresionaccording to the ALSYMPCA study criteria. 
• 
Determination percentage of PSA progresion. 
• 
Alkaline phosphatase level response (AF), normalization of alkaline phosphatase level, 
according to the ALSYMPCA study criteria. 
 
Molecular aspects 
• 
Assessment of AR-V7 mutation evolution during the study treatment. 
• 
Determination changes in CTCs number during the study treatment. 
3. STUDY OVERVIEW 
3.1. Type of study 
This is a multicenter, single-arm, open-label, non-controlled phase IIa clinical trial. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
22 of 67 
 
3.2. Study schedule 
The design of this study is divided into three well-defined phases: 
• 
Screening phase 
During this phase, subject eligibility is determined, including the documentation of baseline 
characteristics. This phase of the study will begin once the informed consent is signed by the 
patient and the procedures to be performed are described in section 5.1 of the protocol. 
• 
Treatment phase: 
When a patient is identified and all the study screening criteria have been met, a baseline 
blood sample will be collected to perform CTCs the patient will be treated with radium-223 at 
a dose of 55 kBq (after 2015 NIST implementation) per kilogram body weight, given at four-
week intervals for six intravenous (IV) injections.  
Patients will receive study treatment according to the protocol and will be prematurely 
discontinued if one of the following situations arises: 
 
• 
Disease progression is confirmed radiologically and unequivocally. An event for 
progression will be determined by The Prostate Cancer Clinical Trials Working Group 
(PCWG2) modified criteria defined as the time from inclusion to the first event in clinical, 
radiological, or biochemical progression, or death as[21]: 
 
- Bone metastases: The appearance of ≥ two new lesions, and, for the first reassessment 
only, a confirmatory scan performed six or more weeks later that shows a minimum of two or 
more additional new lesions. The date of progression is the date of the first scan showing the 
changes. 
- Soft-tissue lesions: Assesed according to the Response Evaluation Criteria in Solid Tumors 
(RECIST criteria) version 1.1.[22]. 
- Symptoms: Consider independently of other outcome measures. Document pain/analgesia 
at entry and measure repeatedly at three- to four-week intervals. Ignore early changes (≤ 12 
weeks) in pain or health-related quality of life (HRQOL) in the absence of compelling evidence 
of disease progression. Confirm progression of pain or HRQOL endpoints ≥ three weeks later. 
- Clinical deterioration: Consider independently of other outcome measures. A deteriorating 
patient is one who moves from one clinical state to a worse clinical state which increases their 
individual risk of morbidity, including organ dysfunction, protracted hospital stay, disability, or 
death.[23]. 
• 
AEs which, according to the protocol or in the opinion of the investigator, can cause 
serious or permanent damage or which rule out further treatment with the study drug. 
• 
Major study protocol non-compliance. 
• 
Patient’s withdrawal from the study. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
23 of 67 
 
• 
Dead. 
• 
Study is canceled by the Sponsor. 
 
Patients may continue receiving commercial radium-223 (Xofigo®), if it is found to offer clinical 
benefits in the opinion of the investigator. 
• 
Follow-up phase:  
Once the treatment phase is completed, patients will enter a follow-up period with radiological 
tumor assessment every three months (±7 working days) until disease progression and safety 
evaluation during 2 years from the last dose of study treatment. If patient discontinued 
treatment for any reason other than progression, tumor reevaluation will be included in the 
assessment. After disease progression, a safety follow-up visit will be performed within three 
following months and 2 years after the last dose of study treatment (including survival status 
and post-study anticancer therapy evaluation). Safety evaluation after progression will include 
follow-up of symptomatic skeletal related events and overall survival. 
3.3. General concomitant medication and additional assistance guidelines 
Concomitant treatment and prior medication are defined as non-investigational medicinal product 
(non-IMP). Concomitant treatment includes any prescribed medication or phytotherapy between 
the 28 days prior to the administration of the first treatment dose until disease progression. All 
concomitant treatments will be recorded. After this time, information will only be collected on any 
anti-cancer drugs and other possible medications for symptomatic skeletal related events taken 
by the patient until end of study (EoS). 
Information on concomitant medication will include start date, end date, brand or generic name, 
route of administration, dose, and treatment indication.  
The following concomitant tratments are permitted during the study: 
• 
Erythropoiesis-stimulating agents (ESA) are permitted (such as Procrit®, Aranesp®, 
Epogen®) for the supportive treatment of anemia. Blood transfusions are permitted during 
the study. 
• 
The prophylactic use of granulocyte-colony stimulating factors (G-CSF; GM-CSF) is not 
allowed during the first treatment cycle, but can be used for cases of neutropenia arising 
during treatment, in accordance with theNational Comprehensive Cancer Network 
(NCCN) guidelines[24]. In any case, the investigator should request approval from the 
medical scientist. 
• 
The use of medication for the treatment of diarrhea, nausea, or vomiting is permitted. 
• 
Approved bone-targeting therapy must have been on stable doses for at least four weeks 
prior to start of study drug at day 1. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
24 of 67 
 
• 
Any medications deemed necessary to ensure patient safety and well-being may be 
administered at the discretion of the investigator. 
3.4. Prohibited therapies 
Cytotoxicchemotherapy, othersystemic radioisotopes, radiotherapy, abiraterone acetate, 
enzalutamide, any antiandrogen, or other investigational drugs shouldnotbe used during the 
treatment period.Ifsuchtreatments are to be introduced during the treatment period, further 
studydrug administrations must be discontinued and treatment with the disallowed therapy 
should not be initiated until at least four weeks after last studydrug administration, if possible. 
3.5. Duration of study treatment (treatment phase) 
The study treatment period is defined as the time elapsed between the first treatment dose and 
the last dose of treatment administered. 
The study treatment should be interrupted if at least one of the reasons listed in section 3.2 is 
present, and the reason(s) for interruption should be recorded in the patient record and in the 
corresponding case report form (CRF). 
3.6. Duration of post-treatment follow-up period (follow-up phase) 
The efficacy follow-up period is defined as the time relapsed between the last treatment 
administration and disease progression, death, withdrawal of consent, or 34 months after the first 
patient has been included, whichever occurs first. Safety follow-up period is defined as 2 years 
since the last treatment administration. 
3.7. EoS 
The EoS is defined as the Last Patient LastVisit (LPLV) at the end of the safety follow-up period 
(24 months after last dose of treatment ). This is the last timepoint for data collection.  
The last visit for efficacy evaluation  will be take place within three following months after last 
patient’s disease progression, death, withdrawal of consent or 34 months after the first patient 
has been included, whichever occurs first. 
The last visit for safety and overall survival evaluation will be take place 2 years after last dose of 
study treatment of last patient. We include a 2-years extension after the end of the treatment to 
evaluate symptomatic skeletal related events. Additionally, analysis of overall survival will be also 
extended. Contact by telephone is permitted. 
4.  
PATIENT SCREENING 
The following eligibility criteria can be used in the screening of patients for whom the protocol 
treatment is deemed suitable. In order to determine whether this protocol is suitable for a given 
patient, all medical and non-medical criteria should be taken into consideration. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
25 of 67 
 
4.1. Study population 
Patients with mCRPC with asymptomaticprogression while on abiraterone acetate or 
enzalutamide. The progression on enzalutamide or abiraterone acetate will be defined as patients 
who confirm radiographic progression and/or PSA progression with rapid PSA doubling time (less 
than three months). 
The patient’s signed informed consent should be obtained before any trial related activities and 
according to local guidelines. 
4.2. Inclusion criteria 
Patient eligibility will be reviewed and documented by a suitable member of the investigator’s 
study team before the patients are enrolled in the study. 
Patients must meet all the following inclusion criteria to be enrolled in the study: 
• 
Subject is an adult ≥ 18 years at the time of informed consent and has signed informed 
consent before any trial related activities and according to local guidelines. 
• 
Subject has histologically confirmed adenocarcinoma of the prostate without neuroendocrine 
differentiation or small cell features. 
• 
Subject has bone metastases due to the prostate cancer and absence of visceral metastases. 
• 
Subject has a serum testosterone of ≤ 1.7 nmol/L (or ≤ 50 ng/dL) at screening. 
• 
Subject must have received a minimum of 24 weeks of treatment with abiraterone acetate or 
enzalutamide within its approved label indication and has discontinued use at least four 
weeks prior to start of study drug at day 1. 
• 
Prior use of docetaxel is allowed in castration-naïve patients (maximum of six cycles). 
• 
Subject receives and will continue to receive ongoing androgen deprivation with LHRH 
analogue therapy throughout the course of the study or has had a bilateral orchiectomy. 
• 
Subject is asymptomaticfrom prostate cancer, defined as patients with the score on brief pain 
inventory (short form) (BPI-SF) Question #3 must zero and no use of opiate analgesics for 
prostate cancer-related pain currently or anytime within two weeks prior to screening. 
• 
Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 at 
screening. 
• 
Subject receiving bisphosphonate or other approved bone-targeting therapy must have been 
on stable doses for at least four weeks prior to start of study drug at day 1. 
• 
Subject has a life expectancy of more than or equal to 12 months. 
• 
Subject agrees not to participate in another interventional study while on study drug. 
• 
Subject and his female partner who is of childbearing potential must use two acceptable 
methods of birth control (one of which must include a condom as a barrier method of 
contraception) starting at screening and continuing throughout the study period and for six 
months after final study drug administration. 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
26 of 67 
 
4.3. Exclusion criteria 
Any patient meeting ANY of the following criteria will be excluded from the study: 
• 
Subject has received any anti-neoplastic therapy (including ketokonazol and chemotherapy) 
following abiraterone acetate or enzalutamide discontinuation and prior to start of study drug 
at day 1. 
• 
Subject has known or suspected brain metastases or active leptomeningeal disease. 
• 
Subject has concurrent disease or any clinically significant abnormality following the 
investigator’s review of the physical examination and safety laboratory tests at screening, 
which in the judgment of the investigator would interfere with the subject's participation in this 
study or evaluation of study results. 
• 
Subject has a history of another invasive cancer within three years prior to screening, with 
the exceptions of non-melanoma skin cancers or a non-infiltrating muscle bladder cancer that 
have a remote probability of recurrence in the opinion of the investigator in consultation with 
the medical scientist. 
• 
Subject had major surgery within one month prior to screening. 
• 
Subject has received investigational therapy within 28 days or 5 half lives, whichever is longer, 
prior to start of study drug at day 1. 
• 
Subject has absolute neutrophil count < 1,500/μL, platelet count < 100,000/μL, and 
hemoglobin < 6.25 mmol/L (or < 10 g/dL) at screening (Note: Subjects must not have received 
any growth factors or blood transfusions within seven days of the hematologic laboratory 
values obtained at screening). 
• 
Subject has total bilirubin > 1.5 times the upper limit of normal (ULN) at screening, except for 
subjects with documented Gilbert’s syndrome. 
• 
Subject has creatinine > 2.5 mg/dL at screening. 
• 
Subject has albumin ≤ 30 g/L (or ≤ 3.0 g/dL) at screening. 
 
5. STUDY ASSESSMENTS AND PROCEDURES 
5.1. Screening phase: Patient enrollment procedures 
Study-specific assessments performed during the screening phase: From Day 0 (patient 
allocation) to day 28 (to confirm remaining screening criteria during days 1-28 after day 0 of the 
screening phase). 
Written informed consent from the patient must be signed before performing any study procedure 
(before screening assessment).By giving their consent, patients will be informed as to the nature 
of the study drug and will receive pertinent information regarding the study objectives, possible 
benefits, and potential AEs. They will also receive information on the follow-up procedures and 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
27 of 67 
 
possible risks they will be exposed to. This document also informs patients about how biological 
samples will be obtained and collected and its legal implications. After receiving the document, 
the patient will read it (or receive information verbally before witnesses) and will sign the 
previously approved informed consent. The patient will receive a signed copy of the informed 
consent. The patient can withdraw their consent and discontinue the study, this will not affect any 
future medical treatment. 
At inclusion: 
1. The Sponsor will request the patient’s demographic and clinical data related to screening 
criteria.  
2. Each patient will be given a Unique Patient Number (UPN) for this study, provided by the 
Sponsor. All data will be recorded in the appropriate CRF using this identification number. 
This number will be provided to the central laboratory to ensure traceability of study samples. 
Confirmation of patient’s eligibility for study participation will be recorded in the CRF. The 
investigator is responsible for safeguarding patient information (e.g., age, name, address, 
telephone number, social security number, and study identification number), ensuring access to 
this information by Health Authorities if necessary. These records will remain confidential for the 
period of time stipulated by current legislation. 
The following will be obtained during the screening phase: 
• 
Anamnesis, medical history, and assessment of symptoms. 
• 
Physical examination and measurement of height, weight, vital signs, and performance 
status. 
• 
Basic blood test that includes hematological test [hemoglobin, hematocrit, red blood cell 
count, platelet count, white blood cell count (WBC) with differential count (neutrophils, 
lymphocytes, monocytes, eosinophils and basophils)], coagulation, chemistry with renal 
function analysis (serum creatinine, creatinine clearance according to the Cockroft-Gault 
formula), liver function [aspartate transaminase (AST), alanine transaminase (ALT), 
Alkaline phosphatase (AF), gamma-glutamyl transferase (GGT), total and direct bilirubin], 
glucose, sodium, potassium, calcium, chloride, magnesium, uric acid, total protein, 
albumin, and lactate dehydrogenase. 
• 
PSA and testosterone determination. 
• 
BPI-SF. 
• 
HRQoL questionnaire (FACT-P, Version 04). 
• 
Blood sample for translational study, which is then sent to central laboratory. 
• 
Assessment of concomitant medications (as it is specified in section 3.3). 
• 
Radiological tumor assessments [torax, abdomen, and pelviscomputerized axial 
tomography(CT) scan or magnetic resonance imaging (MRI), and bone scan] prior to start 
first cycle.  


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
28 of 67 
 
Results of standard of tests or examinations available performed as part as clinical practice prior 
to obtaining informed consent and within 28 days prior to treatment start may be used; such tests 
do not need to be repeated for screening. 
 
5.2. Treatment phase: Assessments 
All screening assessments must be completed and reviewed to confirm that patients meet all 
eligibility criteria before treatment starts (day 1). The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
Visits are organized in programmed cycles of 28 days (if there are no delays in treatment owing 
to the occurrence of a side effect). Adjustment of dose level is not permitted. Dose delays are 
permitted, as described in section 6.11. All visits must occur within ± 7 working days from the 
scheduled date, unless otherwise noted in the schedule of assessments. All assessments will be 
performed on the day of the specific visit unless a time window is specified. Assessments 
scheduled on the day of study treatment administration should be performed prior to study 
treatment administration unless otherwise indicated. If a mandatory procedure described in the 
protocol falls on a bank holiday and/or weekend, this procedure should be performed on the day 
before or after the holiday (i.e. within a period of ± 3 working days). 
Local laboratory tests scheduled for day 1(before treatment) of all cycles must be performed within 
72 hours prior to confirm to the patient if treatment can be followed up. The results of local blood 
tests should be reviewed, and this review recorded before administration of the study treatment. 
Specific study assessments during treatment phase: 
 
During basic safety visits: Day 1of each cycle (every four weeks): 
• 
Assessment of symptoms. 
• 
Physical examination and measurement of weight, vital signs, and ECOG performance 
status. 
• 
Basic blood test that includes blood count, coagulation, chemistry with renal function 
analysis (serum creatinine, creatinine clearance according to the Cockroft-Gault formula), 
liver function (AST, ALT, AF, GGT, total and direct bilirubin), glucose, sodium, potassium, 
calcium, chloride, magnesium, uric acid, total protein, albumin,and lactate 
dehydrogenase. 
• 
PSA determination. 
• 
HRQoL questionnaire (FACT-P, Version 04). 
• 
Assessment of concomitant medications. 
• 
Assessment of AEs. 
• 
Survival. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
29 of 67 
 
During full visits: Day 1 of each cycle every three cycles (every 12 weeks): 
• 
Assessment of symptoms. 
• 
Physical examination and measurement of weight, vital signs, and ECOG performance 
status. 
• 
Basic blood test that includes blood count, coagulation, chemistry with renal function 
analysis (serum creatinine, creatinine clearance according to the Cockroft-Gault formula), 
liver function (AST, ALT, AF, GGT, total and direct bilirubin), glucose, sodium, potassium, 
calcium, chloride, magnesium, uric acid, total protein, albumin,and lactate 
dehydrogenase. 
• 
PSA determination. 
• 
HRQoL questionnaire(FACT-P, Version 04). 
• 
Assessment of concomitant medications. 
• 
Assessment of AEs. 
• 
Tumor assessment: torax, abdomen, and pelvisCT scan or MRI, and bone scan prior to 
start of cycle every three cycles, every 12 weeks, until progression disease. 
• 
Survival. 
Blood assessment schedule for translational study: 
• 
Blood draws prior to the start of study treatment, at the end of treatment and at the time 
to documented progression disease. 
 
Biological sampling: 
The first blood samples should be taken before starting study treatment (see appendix3 for more 
details on blood sampling procedures). The following samples should be taken at the end of 
treatment and at the time of disease progression. 
At the time of site activation, the Sponsor will provide streck cell-free DNA BCT tubes  as well as 
labels for the storage and transport of samples. No other tubes or labels should be used for this 
study. If more tubes and labels are required, these should be requested from the Sponsor in 
writing at least three weeks before they are required (see appendix 3). 
Anamnesis and demographic data: 
Anamnesis includes clinically significant diseases, surgical interventions, history of cancer 
(including prior antineoplastic treatments and procedures), history of smoking, alcoholism, drug 
addiction, as well as any medications (e.g., prescribed drugs, over-the-counter drugs, medicinal 
plants, homeopathic remedies, or food supplements) used by the patient in the 28 days prior to 
screening visit. Demographic data will include age, sex, and self-reported race/ethnicity. 
Vital signs:  


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
30 of 67 
 
These will include the measurement of height (only during screening), weight, respiratory rate, 
heart rate, blood pressure, and body temperature. Abnormal or significant changes in vital signs 
from baseline should be recorded as AEs, if appropriate. 
Physical Examination:  
A complete physical examination should include an examination of head, eyes, ears, nose, and 
throat as well as cardiovascular, dermatological, musculoskeletal, respiratory, digestive, 
genitourinary, and neurological systems. Changes to abnormalities identified during the baseline 
period should be recorded at all subsequent physical examinations. New or worsening 
abnormalities should be recorded as AEs, if applicable. 
Physical exams should also include, as part of tumor assessment, evaluation of presence and 
degree of increase of lymph nodes, hepatomegaly, and splenomegaly. Limited physical exams 
will focus on symptoms. 
Response and tumor assessments: 
Tumor response will be assessed for all patients, unless they withdraw from the study for any 
reason not attributable to disease progression confirmed radiologically or clinically and who have 
not received an acceptable complete assessment of the disease. The non-measurable disease 
should be documented at screening and be re-assessed at every tumor assessment thereafter.  
The initial assessment of tumor response will be performed at the end of cycle three. 
Subsequently, an efficacy follow-up will be carried out for all patients every 12 weeks ±7 working 
days during the study until disease progression, the patient withdraws their consent, or death, 
whichever comes first. In this study, response and disease progression will be assessed using 
the PCWG2 guidelines for bone disease and the RECIST criteria version 1.1 for soft-tissue 
disease. Radiographic disease progression in bone will require persistence of new lesions on a 
confirmatory bone scan performed at least six weeks later. Soft-tissue progression will not require 
a confirmatory scan for purposes of analysis (Appendix 2: Response Evaluation Criteria in Solid 
Tumors Guidelines (RECIST criteria) version 1.1). 
A torax, abdomen, and pelvis CT scan or MRI, and a bone scan must be performed at screening 
(no more than 28 days before the first trial treatment). Tumor assessments should include an 
assessment of all known and/or suspected sites of the disease wherever possible. Patients should 
have a series of selected lesions that can be assessed at each tumor assessment.The same 
radiographic procedure employed at screening should be used throughout the study (e.g., the 
use of the same contrast protocol for CT scans). 
Laboratory assessments: 
Laboratory tests will be performed in accordance to local standard treatment and clinical 
indications before treatment administration. These values should include: blood count, 
coagulation, chemistry with renal function analysis (serum creatinine, creatinine clearance 
according to the Cockroft-Gault formula), liver function (AST, ALT, AF, GGT, direct and total 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
31 of 67 
 
bilirubin), glucose, sodium, potassium, calcium, chloride, magnesium, uric acid, total protein, 
albumin, lactate dehydrogenase, PSA, and testosterone. 
ECOG performance status:  
Performance status will be determined using the ECOG performance status scale (see table 
below). Wherever possible, the patient’s performance status should always be assessed by the 
same personnel throughout the study. 
 
Table 1. ECOG performance status scale 
Grade 
Scale 
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 selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead. 
(http://www.ecog.org/general/perf_stat.html) 
 
AEs and toxicity to treatment: 
Safety and tolerability of all patients will be closely monitored throughout study treatment and the 
follow-up period using the NCI-CTCAE version 4.0[25]. Patients will be assessed in order to detect 
any side effects before administering new study treatment during each treatment visit. Treatment 
will only be administered if clinical evaluation and local laboratory test results are acceptable. 
 
5.3. Follow-up phase 
Patients who complete the study treatment during its active treatment phase will enter a follow-
up period with radiological tumor assessment every three months (±7 working days) until 
documented disease progression and safety evaluation during 2 years from the last dose of study 
treatment. If patient discontinued treatment for any other reason than progression, tumor 
reevaluation will be included in the assessment. 
- 
Assessment schedule after progression or at the end of treatment for any other reason: After 
progression or at the end of treatment for any other reason the following assessments will be 
performed within a period of 28 days (if end of treatment is not confirmed in some of the 
scheduled full visits): 
• 
Assessment of symptoms. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
32 of 67 
 
• 
Physical examination and measurement of weight, vital signs, and ECOG performance 
status. 
• 
Basic blood test that includes blood count, coagulation, chemistry with renal function 
analysis (serum creatinine, creatinine clearance according to the Cockroft-Gault formula), 
liver function (AST, ALT, AF, GGT, direct and total bilirubin), glucose, sodium, potassium, 
calcium, chloride, magnesium, uric acid, total protein, albumin, and lactate 
dehydrogenase. 
• 
PSA determination. 
• 
HRQoL questionnaire(FACT-P, Version 04). 
• 
Assessment of concomitant medications. 
• 
Assessment of AEs. 
• 
Tumor assessment: torax, abdomen, and pelvisCT scan or MRI, and bone scan. 
• 
Blood sample for translational study, which is then sent to central laboratory. 
• 
Survival. 
After disease progression, a safety follow-up visit will be performed within three following months 
and 2 years after last dose of study treatment (including survival status and post-study anticancer 
therapy evaluation). Safety evaluation after progression will include follow-up of symptomatic 
skeletal related events and overall survival. Contact by telephone is permitted. 
In addition, any events ≥ grade 2 will be followed until improvement to baseline levels is observed, 
complete recovery or resolution to grade 1, consent is withdrawn by the patient, patient death, or 
until follow-up is no longer possible. 
 
5.4. Assessment schedule 
The summary of study assessments will be included in Appendix 1: Schedule of study 
assessments and procedures. 
5.5. Discontinuation of patient, study, or site participation 
Treatment discontinuation: Patients have the right to withdraw from the study at any time and 
for any reason, without being required to state their reasons for doing so. The investigator has 
the right to discontinue a patient from study treatment or from the study for any medical condition 
that the investigator determines may jeopardize the patient’s safety if he continues in the study, 
for reasons of non-compliance (e.g., missed doses, visits), or if the investigator determines it is in 
the best interest of the patient. 
Patients should also be withdrawn from the study treatment if they experience disease 
progression as defined by the RECIST criteria version 1.1. Further details regarding study 
discontinuation due to side effects are described in section 6.11. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
33 of 67 
 
Patients who withdraw from study treatment prematurely will be followed up in accordance to 
section 5.3 except for those patients who withdraw their consent and who do not wish to undergo 
a follow-up. The main reason for discontinuation should be recorded in the appropriate section in 
the CRF. 
Study discontinuation:  
Patients will be withdrawn from the study (e.g., from any subsequent study procedure) for any of 
the following reasons: 
• 
Withdrawal of consent. 
• 
Lost to follow-up. 
If patient is lost to follow-up, site personnel must do their utmost to re-establish contact with the 
patient and determine the reason for their withdrawal. All measures taken to undertake follow-up 
should be recorded. 
When a patient withdraws before the end of the study, the reason for withdrawal should be 
recorded in the CRF and in the original document. Patients who withdraw from the study will not 
be replaced. 
In addition, the Sponsor reserves the right to terminate this study at any time. Reasons for 
terminating the study may include, but are not limited to, the following: 
- 
The incidence or seriousness of AEs in this or other studies indicates a potential health 
risk to patients. 
- 
Patient enrollment is unsatisfactory. 
- 
Data recording is inaccurate or incomplete. 
 
6. STUDY DRUG INFORMATION 
6.1. Study treatment 
Once enrolled in the study, the patient will receive study treatment.  
Patients will be treated with radium-223 at a dose of 55 kBq (1.49 microcurie) per kilogram body 
weight, given at four-week intervals for six IV injections. 
6.2. Drug supply 
The latest version of study document Summary of Product Characteristics (SmPC) for radium-
223 (Xofigo®) includes updated information on this drug. 
The Sponsor will provide radium-223, which will be manufactured by the contract manufacturer: 
Institute for Energy Technology, Isotope laboratories, Kjeller, Norway. The products will be 
produced according to Good Manufacturing Practice (GMP), and will be delivered in a glass vial, 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
34 of 67 
 
ready-to-use, with a certified activity. Radium-223 will be shipped in a lead container and type A 
radioactive package according to international transportation guidelines for radioactive materials. 
The alpha-pharmaceutical radium-223 is a ready-to-use, sterile, non-pyrogenic, clear, and color 
less aqueous solution of 223RaCl2 for IV administration.The product isisotonic and has a pH of 
6.0-8.0 with a pre-calibration of 14days.  
Single-use vials contain 6 mL solution at concentration of 1100 kBq/mL (27 microcurie/mL) at 
the reference date with a total radioactivity of 6.6 MBq the reference date (after 2015 NIST 
implementation). When administered on a day other than the reference day, the volume should 
be corrected according to the physical decay table. 
Radium-223 has a shelf life of 28 days from production day, when stored at ambient temperature. 
The shelf life has been demonstrated for temperatures from cold storage (2-8°C) up to 40°C. In 
addition, it has been shown that the product qualityis not jeopardized upon freezing. All study 
drugs will be labeled according to the requirements of local law and legislation. Label text will be 
approved according to the Sponsor’s agreed procedures. 
For all study drugs, a system of numbering in accordance with all requirements of GMP wil be 
used, ensuring that each dose of study drug can be traced back to the respective bulkware of 
the ingredients. Lists linking all numbering levels will be maintained by the Sponsor. A complete 
record of batch number and expiry dates for all study treatments as well as the labels will be 
maintained in the Sponsor study file. 
Once the study has ended, patients may continue receivingcommercial radium-223, if it is found 
to offer clinical benefits in the opinion of the investigator 
6.3. Dosage and administration 
Written information about radium-223 and instruction about handling and injection of radioactive 
material will be provided to study personnel.  
In general, the administration of radioactive drugs involves a potential risk for third parties, due 
to radiation from thepatient and due to possible contamination by spilling urine or feces. When 
radium-223has been injected intravenously into apatient, the risk for external radiation exposure 
to third parties is extremelylow, due to the short range of the alpha particlesand the low portion 
of beta and gamma radiation.  For these reasons the product can be administered on an out-
patient basis. To minimize the risk of contamination, the patient and his caregivers will receive 
instructions regarding hygiene precautions to abide by after receiving the radioactive 
drugaccording to the investigational site radiation protection guidelines. 
6.4. Dose calibration 
Radium-223 can be measured in a normal dose calibrator instrument. When written approvals for 
the use of radium-223 from the Radiation Protection Agencyfor the specific center have been 
received bythe Sponsor, a vial of radium-223 for technical use will be sent to the 
studycenter.Different clinical study centers possess dose calibrators from various suppliers; thus, 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
35 of 67 
 
the isotope calibration factor maydiffer from center to center. Consequently, each center must 
perform the radium-223 dial setting on their relevant dose calibrator(s). For dial setting, the clinical 
studycenter will receive a sealed vial containing a radium-223 solution for calibration only. The 
vial is identical to the vials used for studytreatment. The amount of radium-223 in the vial will be 
stated on the label. Instructions for the dial setting, including the calibration log form, will be 
enclosed with the dispatch of the calibration sample. 
6.5. Dose handling 
Ordering of study drug will be done using Drug Order Form, the site will send this request to 
MedSIR before each planned administration and MedSIR will manage the study drug shipment 
with Bayer. The radium-223 vials must be stored inside their lead container in a secure facility. 
The study drug should be used within 28 days of production.  
Radium-223 is an alpha-emitting pharmaceutical and should be received, used and 
administered only by authorized persons in designated clinical settings. The receipt, storage, 
use, transfer, and disposal aresubject to the regulations and/or appropriate licenses of the 
competent official organization. Radiopharmaceuticals should be prepared bythe user in a 
manner which satisfies both radiation safety and pharmaceutical qualityrequirements. 
Appropriate aseptic precautions should be taken. 
Control measurements of both the radium-223 vial (before and after dispensing) and syringes 
(before and after administration) are performed as part of the clinical trial documentation.All 
administrations of radium-223 arebased on the certified activityof radium-223 at the calibration 
date. 
6.6. Dose calculation 
The dosage of radium-223 is 55 kBq per kilogram body weight. The total activity to be injected 
will be calculated volumetrically using the patient’s bodyweight on the dayof injection, the 55 kBq 
per kilogrambodyweight dosage level, and the decaycorrection factor (DK) to correct for 
physicaldecayof radium-223 (after NIST implementation). A table with DKs according to 
physicaldecayof the study medication will be provided with each vial of radium-223. The total 
amount (volume to be drawn into the syringe) to be administered to apatient should be calculated 
as follows: 
 
Body weight (kilograms) x 55 kBqper kilogram body weight 
---------------------------------------------------------------------------------- = Volume to be injected (mL). 
DK x 1100 kBq/ml 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
36 of 67 
 
6.7. Dose preparation 
Personnel should use appropriate protective clothing and equipment during syringe filling and 
application to prevent contamination with the radioactive solution (lab coats, medical 
gloves/protective glasses). Sites should adhere to all relevant radiation safetyregulations as 
prescribed by local authorities administering their site radiation license, including ALARA 
principles. 
Filling of the syringe should take place in a safetybench or similar cabinet in the 
Radiopharmacy/Nuclear Medicine department. The individual responsible for studydrug 
preparation will draw the correct volume of study drug into a syringe. The size of the syringe 
should be chosen according to the applied volume to reach the required dosing accuracy. 
Radium-223should not be diluted or mixed with any solutions. If the vials have been stored in a 
refrigerator, they should be left at room temperature for one hour prior to use, since cold material 
should not be injected in a patient. 
 
6.8. Dose administration 
Before administration of study drug, the patient must be well hydrated and should be instructed 
to drink ad libitum.Aseptic technique should be used in the administration of radium-223. The 
syringe should be handed over to the individual who will perform the injection. The study 
medication will be administered as a slow bolus IV injection over one minute. After 
administration, the equipment used in connection with the preparation and administration of 
drug is to be treated as radioactive waste and should be disposed in accordance with hospital 
procedure for the handling of radioactive material. Information about radium-223 and 
instruction about handling and injection of radioactive material will be given to study personnel. 
6.9. Medication errors and overdose 
Medication errors in this study may arise when the drug is administered at the wrong time or when 
the wrong dose strength is taken. Patient medication errors should be recorded in the relevant 
section in the CRF. In the event of an error in the administration of the medication, the Sponsor 
should be informed immediately. 
Medication errors must be reported irrespective of the presence of an associated AE/SAE, 
including: 
• 
Medication errors involving patient exposure to the IMP. 
• 
Any possible medication errors or use of the medication not defined in the protocol which 
implicate the participating patient or not. 
Regardless of whether the medication error is accompanied by an AE or not, in the judgment of 
the investigator, the medication error should be recorded in the AE page. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
37 of 67 
 
6.10. 
Treatment compliance 
Patients will receive treatment under the supervision of a physician licensed in the administration 
of radioisotopes. Personnel will check the administration volume and total radioactivityinjected.  
The activitydose (total and per bodykilogram) will be recorded in the source data and the 
appropriate CRF. 
6.11. 
Dose adjustments 
Everyeffort will be made to administer the full dosing regimenofradium-223.  Adjustment of dose 
level is not permitted.Studyvisits during the treatment period should occur at four weeks intervals 
(within a window ± 7 working days). 
Dosing delays may be instituted under the following situations: 
 
• 
Disease progression: 
 
In this patient population, disease progression is expected. Bone pain is a prominent 
symptom; other symptoms mayinclude fatigue, nausea, anorexia, depression, constipation 
(also secondaryto opioids), bowel and bladder symptoms, lymphedema, neurological, and 
hematological complication as well as metastases to other organs, such as liver and lung.The 
investigator should delay cytotoxic chemotherapy, other systemic radioisotope, radiotherapy, 
or other investigational drug until the follow-up period.  If such treatments have to be given 
during the treatment period, further study drug administrations must be discontinued. Patients 
with disease progression may continue treatment at the Investigator’s discretion. 
 
 
• 
Myelosuppression: 
 
Treatment-related changes in hematology parameters may occur: 
 
- 
If apatient experiences grade 3 or 4 neutropenia, thrombocytopenia, or anemia lasting 
≤ 14 days, the administration of studydrug should be delayeduntil recoveryto grade 2 or 
better. A delay of up to 4 weeks is permited. 
 
- 
If a patient experiences grade 3 or 4 neutropenia, thrombocytopenia, or anemia lasting 
>14 days, further study drug administrations must be discontinued. 
 
- 
Blood transfusion is acceptable between studydrug administrations. Use of biologic 
response modifiers, such as G-CSF or GM-CSF, is allowed in the management of 
acute toxicity. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
38 of 67 
 
 
• 
Gastrointestinal events: 
 
- 
Diarrhea. Diarrhea should be treated as per local practice. A further dose of study 
medication should not be given before diarrhea is recovered to no higher than CTCAE 
grade2. 
 
- 
Nausea/Vomiting. Nausea or vomiting should be treated as per local practice. A further 
dose of study medication should not be given before nauseaor vomiting is recovered to 
no higher than CTCAE grade 2. 
 
• 
Surgical intervention: 
 
If surgery is required, the patient should continue with studytreatment, if this is 
considered safe in the treating investigator’s opinion.  The surgeon needs to be notified 
that thepatient has been given radioactive drug, and needs to follow the guidelines for 
radioactive protection. 
 
• 
Non-pathological fractures: 
 
For traumatic fractures in weight-bearing bones during treatment phase, the 
study drug administration should be delayed for two to four weeks from the time 
of fracture. 
 
• 
Any other toxicity: 
Local practice will apply. A dose delay of more than four weeks (maximum eight 
weeks between two injections) will lead to study drug discontinuation. 
6.12. 
Possible drug interactions 
No formal clinical drug interaction studies have been performed with radium-223. Any medications 
deemed necessary to ensure patient safety and well-being may be administered at the discretion 
of the investigator with the exceptions indicated in section 3.4. 
7. SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
Safety assessments will consist of monitoring and recording AEs, adverse events of special 
interest (AESI), and SAES as defined in the protocol; measurement of blood count and chemistry 
values specified in the protocol; and the measurement of vital signs and other tests defined in the 
protocol which are deemed important to the safety assessment of the study drug(s). 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
39 of 67 
 
The Sponsor or its designee is responsible for reporting SAEs to the competent authorities, other 
applicable regulatory authorities, and participating investigators, in accordance with International 
Conference on Harmonization (ICH) guidelines, European Clinical Trials Regulation (Regulation 
(EU) No. 536/2014), and/or local regulatory requirements. 
The Sponsor or designee is responsible for reporting unexpected fatal or potentially life-
threatening events related to the use of the study drug to the Health Authorities and relevant 
authorities, by fax within seven calendar days of learning of its occurrence. The Sponsor or 
designee will report any other significant expeditable SAEs related to the use of the study 
medication to the corresponding competent authorities (in accordance with local guidelines), in 
the form of a written safety report within 15 calendar days. 
7.1. Definitions of AEs 
An AE is defined as an incident that is harmful to the health of the patient who has been treated 
with an IMP as part of a clinical trial, even though there may not be a causal relationship between 
the two. Therefore, an AE can be any unfavorable and/or unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an IMP, regardless 
of whether it is considered to be related to the investigational product or not. Abnormal test results 
should only be reported as AEs if they meet any of the following criteria, are associated with 
concomitant symptoms, and cannot be defined in general diagnostic terms. This includes 
abnormal symptoms and test results, or symptoms that call for additional diagnostic testing, 
pharmacologic intervention or surgery, a change in study drug dose or withdrawal from the study, 
those requiring additional concomitant drug treatment, or those that are considered an AE by the 
investigator or Sponsor. 
The causal relationship between an AE and the IMP will be defined as follows: 
Unrelated: The time relationship between the AE and the administration of the IMP makes a 
causal relationship between the two highly unlikely, or the patient’s clinical status or the study 
procedures/conditions sufficiently explain the cause of the AE. 
Related: The time relationship between the AE and the administration of the IMP makes a causal 
relationship between the two very likely, and the patient’s clinical status or the study 
procedures/conditions do not sufficiently explain the cause of the AE. 
The investigator will assess each AE to determine whether or not there exists a reasonable 
possibility that the AE is related to radium-223. 
Toxicities will be reported using the descriptions and grade scales provided by the NCI-CTCAE 
version 4.0. A copy of the NCI-CTCAE criteria version 4.0 can be downloaded from the CTEP 
website (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-4_QuickReference_5x7.pdf).  
When reported, the severity of an adverse event will be classified as one of the following:  


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
40 of 67 
 
- 
Mild - easily tolerated AE: It does not interfere with daily activities. CTCAE grade 1. 
- 
Moderate: It causes some disruption of daily activities, may require intervention or 
treatment. CTCAE grade 2  
- 
Severe: Considerable disruption of daily activities, need for hospitalization and/or surgical 
intervention or treatment. CTCAE grade 3 or 4. 
- 
Fatal: Death. CTCAE grade 5 
- 
Not applicable: Abnormalities in laboratory tests that are clinically significant and 
asymptomatic, or abnormal assessments not covered by the CTCAE scale, even though 
they are considered an AE. 
A mild, moderate, or severe AE may or may not be serious. These terms are used for describing 
the severity of a specific event. Nevertheless, the medical significance of a severe event may be 
considered relatively minor (such as a severe headache) and may not be necessarily serious. For 
example, nausea lasting several hours may be considered severe, but may not be clinically 
serious. A fever of 39 °C which is not considered severe, may become serious if it results in a 
one-day hospital stay. Seriousness, rather than severity, serves as a guide for determining 
whether the event should be reported to authorities. 
Adverse reactions to medicines: Any harmful and unexpected responses to an IMP (i.e. when 
there is a at least reasonable possibility that there is a causal relationship between the IMP and 
the AE) that are related to any dose should be considered an adverse reaction to the medicine. 
In the case of marketed drugs, an adverse reaction to medicine is defined as a drug response 
that is harmful and unexpected and is produced at the dose that is normally administered to 
human subjects for prophylaxis, diagnosis or treatment of diseases, or to alter physiological 
functions. 
Anunexpected adverse reaction to a medicine is defined as an adverse reaction whose nature or 
severity is not consistent with the information on the product. 
SAEs: By definition, a SAE is defined as any event that: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires hospitalization or prolongs existing hospitalization. 
• 
Results in persistent or significant disability/incapacity (incapacity is defined as a 
significant disruption in a person’s ability to perform normal life activities). 
• 
Constitutes a congenital anomaly/birth defect. 
Definition of life-threatening: An AE islife-threatening if the patient was at immediate risk of death 
due to the event; i.e. not including a reaction that could have caused death if it had been more 
serious. For example, a drug-induced hepatitis that resolved without signs of liver failure will not 
be considered life-threatening, even though drug-induced hepatitis can be fatal. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
41 of 67 
 
Definition of hospitalization: AEs that require hospitalization are considered serious. In general, 
hospitalization is considered as such when the patient has stayed (usually overnight) at a hospital 
or emergency room for observation or treatment that could not have been performed in a doctor’s 
office or outpatient site. If there is some doubt as to whether the hospital stay can be considered 
“hospitalization” or whether it was necessary or not, the AE should be considered serious. 
Hospitalization for scheduled surgery or standard clinical procedures which are not the result of 
an AE will not be considered an AE. If an incident arises during the procedure that is considered 
harmful, this should be reported as an AE and should be designated “serious” or "not serious” as 
per the standard criteria. 
Definition of an event that is clinically or medically significant: Significant medical events that do 
not have a fatal outcome, regardless of whether they are life-threatening or require hospitalization, 
may be considered SAEs when, according to the appropriate medical opinion they put the 
patient’s life at risk and may require medical or surgical intervention to prevent any of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
which requires intensive treatment in an emergency room or at home; blood dyscrasias; 
convulsions that do not result in hospitalization; or development of drug dependency or drug 
abuse.Clinically/medically significant events must be reported as SAEs. 
For this clinical study and, according to this protocol, SAEs and hospitalizations related solely and 
unequivocally to the progression of the established tumor disease will not be treated as SAEs 
with regards to reporting obligations. 
If the investigator becomes aware of a SAE at any time after the end of administration of study 
treatment and believes that it is possibly related to the study treatment (serious adverse 
reactions), he/she should notify the Sponsor. 
7.2. Reporting of AEs 
AEs will be collected starting from the first procedure required by the study up to three months 
after patient’s disease progression. Safety evaluation after progression will include follow-up of 
symptomatic skeletal related events until reach 2 years from the last dose of study treatment.   
All study patients who experience AEs will be closely monitored during this time. All AEs should 
be recorded in the CRF. 
All signs, symptoms, and results of procedures with abnormal diagnoses that are clearly related 
should be grouped together and reported as a single diagnosis or disorder wherever possible. 
Any other event that does not fulfill this definition will also be reported separately.  
 
Reporting of SAES and reporting period 
Reporting requirements will comply with all applicable local regulations regarding safety reporting.  


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
42 of 67 
 
All SAEs and AESIs defined in the protocol will be reported to the Sponsor  within a period of 24 
hours from the time the investigator or any other member of the site staff becomes aware of the 
event, as follows: 
• 
Regardless of the study drug received by the patient and whether or not the investigator 
considers this event to be related or not to the study drug, all SAEs and AESIs (as defined 
in this protocol), will be reported to MedSIR immediately, no later than 24 hours after any 
member of the study site staff becomes aware of the event. 
• 
All information regarding the SAE and AESI should be obtained and recorded in full using 
the SAE form and sent to MedSIR.  
• 
Follow-up information, copies of test results, event outcome and the opinion of the 
investigator as to the relationship between the IMP and the SAE and AESI, accompanied 
by other applicable documentation when it is requested, will be sent along with the SAE 
form, if available on the day the event is reported or as soon as possible if it is not. 
• 
The original SAE reporting form of the Sponsor should be kept on file with the 
documentation from the CRF at the study site(s). 
 
All SAE forms will be sent by the investigator or investigator staff to the Sponsorby e-mail and fax 
as indicated below: 
E-mail: farmacovigilancia@experior.es 
Fax: + 34 96 145 21 91 
Follow-up of the SAEs and AESIs will continue until they resolve, a stable outcome is reached, 
patient is lost to follow-up, or the patient dies. 
MedSIR will be responsible for ensuring that events are reported to the European Medicine 
Agency (EMA), competent authorities, within the stipulated period, as needed. 
 
AESIs 
The investigator must report any AESIs to the Sponsor immediately (i.e. within 24 hours of 
learning of its occurrence) regardless of their seriousness (see section 7.2). In this study, AESIs 
include: 
• 
An agent is considered infectious when it is suspected that an infectious agent has been 
transmitted via medication, any organism, virus or infectious particle (e.g.,the prion 
protein that causes transmission of transmissible spongiform encephalopathies), 
pathogenic or not. Transmission of an infectious agent may be suspected due to clinical 
symptoms or laboratory results which indicate the presence of infection in an individual 
exposed to a medicine. This term will only be applied when drug contamination is 
suspected and not to any infections supported by mechanism of drug action, e.g. 
immunosuppression. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
43 of 67 
 
• 
Potential drug-induced liver damage which meets the analytic criteria of Hy’s Law. The 
following laboratory abnormalities are indicative of possible Hy’s Law cases and should 
be reported as AESIs: 
o 
Any increase in AST and/or ALT> 3 times the ULN. 
o 
Simultaneous increase in total bilirubin > 2 times ULN (or clinical jaundice if total 
bilirubin measurements are not available), except for patients who have been 
diagnosed with Gilbert's syndrome. In the case of patients with Gilbert's 
syndrome, an increase in direct bilirubin > 2 times ULN should be used. 
Non-compliance 
Definition: Non-compliance with applicable laws or institutional policies that govern research on 
human subjects to follow-up on ethics committee (EC) decisions. Non-compliance may occur due 
to ignorance or a deliberate decision to ignore the law, institutional policies, or EC decisions. 
Non-compliance should be reported to MedSIR, the principal investigator of the study site and, if 
necessary, to the EC immediately, within 24 hours. 
Serious non-compliance 
Definition: Non-compliance that materially increases the risk of serious harm to patients or other 
persons, or which materially compromises patient rights or well-being. 
Serious non-compliance should be reported to MedSIR, the principal investigator of the study site 
and, if necessary, to the EC immediately, within 24 hours. 
Expedited reporting to Health Authorities 
To determine the reporting requirements in cases of a single AE, the Sponsor will assess the 
expectedness of these events using the radium-223 SmPC. 
The Sponsor will compare the severity of each event and its cumulative frequency as reported in 
the study with the severity and frequency reported in the pertinent source document. 
Reporting requirements are also based on the investigator’s assessment of causality and 
seriousness, which may be updated by the Sponsor as needed. 
7.3. Safety reporting flow chart 
Non-serious AE reporting responsibilities:  
Investigational site 
(completion of CRF) 
 
Data management department of 
CRO and MedSIR (review, 
evaluation, and processing of 
safety data): 
Quarterly lists of non-serious AEs 
 
CRO/MedSIR will provide quarterly 
lists of non-serious AEs for Bayer 
 
 
AESI and SAE reporting responsibilities (as defined in the protocol):  


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
44 of 67 
 
Investigational site 
(SAE report, 24 
hours) 
 
CRO/MedSIR (review, 
evaluation, and 
processing of safety 
information): Reporting 
to CIOMS 
 
 
Expedited safety reports &Periodic Safety e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radium-223 treatment DSUR [DSUR form: Non-commercial Sponsor (MedSIR)] 
n, and processing of safety information): 
DraftDrafting DSUR 
 
Bayer (copy): ASAP 
 
Health authorities, EC in accordance with 
regulatory reporting obligations  
Note:Bayer will send MedSIR an executive summary of Bayern’s DSUR, at the request of MedSIR. MedSIR 
may cross reference Bayern’s executive summary of DSUR. 
 
 
Bayer (review, evaluation, and processing of safety data from sources other than 
those used in this clinical trial): Latest version of IB and IB updates, medical alert 
letters, and any new data that could modify or complement known data on radium-
223, especially any new AEs and data related to radium-223 tolerance that may 
indicate a risk to patients: 
 
 
MedSIR: ASAP 
 
To Bayer (copy):  
• SUSARs & AESIs requiring expedited 
reporting within 15 days 
• Other SAEs, other AESIs & 
pregnancy reports within 30 days 
Expedited safety reports &Periodic Safety 
Line 
Listings 
(PSLLs) 
according 
to 
regulatory reporting obligations (including 
timelines) 
CRO/ MedSIR (review, evaluation, and 
processing of safety information): Drafting 
DSUR): Drafting DSUR 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
45 of 67 
 
Managing safety crisis and safety-related requests from Health Authorities or for 
publications: 
 
In the event of a safety crisis, e.g. cases where safety issues will potentially impact indication(s) or the conduct 
of the study that may give rise to changes in labeling or regulatory actions that limit or restrict the way in 
which radium-223 is used or in cases where the media is involved, the party (MedSIR) where crisis originated 
will contact the other party as soon as possible. Bayer will have final say and control over aspects related to 
the management of the safety crisis regarding. 
MedSIR will not reply to any request related to the safety of radium-223 that it receives from the Health 
Authorities, the media or other sources (publications). Instead, it will direct requests to Bayern in accordance 
with and communicating the deadlines regarding necessary replies. 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
46 of 67 
 
8. STATISTICAL CONSIDERATIONS AND STATISTICAL ANALYSIS PLAN 
8.1. Determination of sample size 
A total of 52 patients will be enrolled into this trial. We expect to include 13 AR-V7-positive and 
39 AR-V7-negative patients. 
8.2. Justification of sample size 
The sample size is determined on the basis of the primary endpoint. The primary endpoint is 
defined as PFS according tothe PCWG2 criteria. We will screen the AR-V7 mutation 
retrospectively, after the patient was included. We expect the number of AR-V7-positive patients 
will be 25% of total sample. Therefore, sample size has been estimated on AR-V7-positivecohort 
to ensure a minimum of 80% power in two cohort analysis. We hypothesized equally efficacy of 
radium-223 in AR-V7-negative and AR-V7-positive cohorts. 
Previous studies in advanced refractory prostate cancer patientstreated with docetaxel plus 
estramustine against mitoxantrone plus prednisone showed a median PFS of 6.3 and 3.2 months, 
respectively[26]. According to these results, excluding a PFS ≤ 3 months while targeting an 
improvement of the PFS ≥ 6.3 months would be a conservative approach to evaluation of the 
radium-223 effect inboth cohorts. The analysis will be performed with one arm one-sided Log-
Rank test. We program a 23 months of accrual period and 11 months of follow-up period 
(maximum follow-up of 34 months). We assume an uniform accrual of 2.26 patients per month 
(both cohorts). A sample size of 52 patients will be needed to attain 80% power at nominal level 
of one-sided alpha of 0.05. Therefore, we expect to include a total sample of 52 patients, 39 of 
them will be AR-V7-negative and 13 AR-V7-positive patients. 
Safety follow-up extension of the study. 
The maximum follow-up of the study for primary and secondary efficacy analysis will be 34 
months. However we will include a 2-years extension after the end of the treatment (April 2019) 
to evaluate bone lesions. Additionally, analysis of overall survival will be also extended.  
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
47 of 67 
 
8.3. Statistical plan 
Unless otherwise mentioned all tests will be two-sided. 
8.3.1. Primary efficacy endpoint 
 
The primary efficacy endpoint is the median PFS achieved with radium-223 treatment. The PFS 
will be evaluated at the first 34 months period of the study. The PFS will not be evaluated at the 
2-years extension of the study for safety. PFS is a composite endpoint defined as the time from 
the start of the radium-223 treatment to disease progression in bone or soft-tissue, symptoms, or 
death, according to the modifiedPCWG2 criteria. Objective radiographic disease progression is 
defined as the presence of at least one of thefollowing conditions: 
 
• 
Bone lesion progression (appearance of ≥ two new bone lesions compared to baseline). 
• 
Soft-tissue lesion progression according to the RECIST criteria version 1.1. 
• 
Presence of symptomatic skeletal events. 
 
Patients with no progression will be censored at the date of their last evaluation. Censoring rules 
are specified in Table 2. 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
48 of 67 
 
Table 2. Censoring rules for PFS 
 
Situation 
Date of progression or censoring 
Outcome 
Progression 
documented 
between 
scheduled visits  
Earliest of: 
• Date of radiological assessment showing new 
lesion (if progression is based on new lesion); 
or 
• Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions); 
or 
• 
Bone lesion progression (appearance of ≥ 
two new bone lesions compared to baseline); 
or 
• 
Presence of symptomatic skeletal events 
(pathological 
fractures, 
spinal 
cord 
compression, radiation or surgery to bone) 
Progressed  
Death before first progression disease 
assessment 
Date of death 
Progressed  
Death between adequate assessment 
visits  
Date of death  
Progressed  
No progression 
Date of last radiological assessment of measured 
lesions 
Censored 
Treatment 
discontinuation 
for 
undocumented progression  
Date of last radiological assessment of measured 
lesions 
Censored 
Treatment discontinuation for toxicity or 
other reason 
Date of last radiological assessment of measured 
lesions 
Censored 
Death or progression after more than 
one missed visit  
Date of last radiological assessment of measured 
lesions 
Censored 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
49 of 67 
 
8.3.2. Secondary endpoints 
 
All efficacy endpoints will be described in both study cohorts (AR-V7-negative and positive) and 
combining both cohorts. 
All efficacy endpoints will be evaluated at the first 34 months period of the study. Additionally, OS 
will be evaluated at the 2-years safety extension after the end of the treatment. The other efficacy 
endpoints will not be evaluated at the 2-years safety extension.  
 
-OS defined as the time from inclusion until death from any cause or the last date the patient was 
known to be alive.  
Patients who are lost to follow-up and the patients who are alive at the date of data cut-off are 
censored at the date the patient was last known alive. Censoring rules are specified in Table 3. 
- Time to first SSE defined as the time from treatment initiation untilSSE (pathological fractures, 
vertebral or non-vertebral, spinal cord compression, radiation or surgery to bone).For all other 
events, the start date of the event/medication/therapy was used as the time of the event. If an 
event has not occurred at the time of the analysis or the patient has been lost to follow-up, the 
time-to-event variables will be censored at the last disease assessment date. 
- Alkaline phosphatase level response, normalization of alkaline phosphatase level(progression 
defined as FAelevation ≥ 25% after 12 weeks). 
- The time from the first study drug administration to when PSA progresion was observed, defined 
as: 1) In subjects with no PSA decline from baseline; a greater than or equal to 25% increase 
from baseline value and an increase in absolute value of greater than or equal to 2 ng/mL, at least 
12 weeks from baseline; 2) In subjects with initial PSA decline from baseline; the time from start 
of treatment to first PSA increase that is greater than or equal to 25% increase and at least 2 
ng/mL above the nadir value, which was confirmed by a second value obtained three or more 
weeks later. 
- Determination percentage of PSA progression(defined as PSA elevation ≥ 25% and ≥ 2 ng/mL 
after 12 weeks). 
-Radiographic progression-free survival (rPFS) depending on AR-V7 status 
 
Predictive biomarkers 
- Assessment of AR-V7 mutation prior to the start of study treatment and at time to documented 
progression disease or treatment end (see Appendix 3). 
-Determination changes in CTCs number prior to the start of study treatment and at time to 
documented progression disease or treatment end (see Appendix 3). 
 
Table 3. Censoring rules for OS 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
50 of 67 
 
Situation 
End date 
Status 
Death during study follow-up 
Date of death 
Death 
The patient is alive at last follow-up 
Date of last follow-up 
Censored 
8.3.3. Analysis sets 
 
We propose to test efficacy and safety of experimental treatment using the full analysis set. We 
include in the analysis all patients that accomplished selection criteria and receive one drug 
exposure.  
8.3.4. Analysis of baseline and demographic variables 
 
The demographics and baseline characteristics including disease history and prior therapy are 
summarized using descriptive statistics. 
8.3.5. Efficacy analysis 
 
Tumor response, bone lesion, SSE evaluation, biochemistry determinations,and predictive 
biomarkers are obtained at investigators' sites. There is not central and independent review of 
evaluations. Methodology for tumor assessment will be according tothe RECIST version 1.1 and 
the PCWG2 criteria. 
8.3.6. Decision rules and adjustment of alpha for primary endpoint 
 
The study will be declared positive if the median PFS of radium-223 in total sample is statistically 
significantly better compared with null hypothesis (p<0.05). 
8.4. Efficacy results 
Primary endpoint 
We will analyze PFS in both cohorts with one arm Log-Rank test. This time endpoint will be 
described with Kaplan-Meier method. We will calculate number and proportion of events and 
median survival time, with corresponding 95% Cl. 
Secondary endpoints 
We will describe the number and percentage of patients with AR-V7 mutation and CTCs at the 
start and at the end of the study. The evolution of these measures in the study will be analyzed 
with Mc Nemar’s test and paired odds ratio (OR) with corresponding 95% CI. 
OS, time to first symptomatic SSE, rPFS and alkaline phosphatase level response (AF) will be 
described with Kaplan-Meier method. Number and proportion of events and median survival time, 
with corresponding 95%Cl, will be calculated. 
Subgroup analysis 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
51 of 67 
 
The AR-V7-negative and positive cohorts at baseline will be compared for all analysis. For timed 
endpoints (PFS, OS,time to first symptomatic SSE, TTP-AF, and TTP-PSA), we will use the 
Kaplan-Meier method and Log-Rank test. For binary outcomes we will use chi-squared or fisher´s 
exact tests. 
Levels of CTCsat the start and at the end of the study will be correlated with timed and binary 
endploints. For timed and binary endpoints we will use cox analysis and logistica regression, 
respectively.  
We also analyse PFS and OS with multivariable Cox proportional hazards models for adjusting 
for AR-V7 status, CTCs levels and relevant baseline covariates, including Gleason score, PSA 
level, number of prior hormonal treatments, the presence or absence of visceral metastases, the 
Eastern Cooperative Oncology Group (ECOG) score, prior use of abiraterone acetate or 
enzalutamide, and the level of full-length (FL) androgen receptor. All tests were two-sided, and P 
values of 0.05 or less were considered to indicate statistical significance. We will examine the 
residuals to assess model assumptions and only first-order interactions will be evaluated. We will 
calculate relative risk (RR) and HR with corresponding 95% CI to compare dichotomous and time 
to event variables, respectively. Up-to-date versions of R will be used to conduct analyses. 
8.5. Safety results 
All safety date will be evaluated at the first 34 months period of the study. Additionally, 
symptomatic skeletal related events will be evaluated at the 2-years safety extension after the 
end of the treatment. 
Analysis of safety-related data will be considered at three levels: 
• 
First, the degree of exposure (dose, duration, number of patients) will be assessed to 
determine the degree to which study safety can be assessed. 
• 
Second, clinically relevant tests, concomitant medications, and reported AEs will be 
described. For AEs, severity, expectedness, causality, relationship, body system, action 
taken, and outcome will be reported. 
• 
Third, SAEs, deaths, and study discontinuations for each study group will be described 
and assessed. 
8.6. Missing data management 
The analysis of the primary and secondary timed endpoints (progression and death) will be based 
on a Log-Rank or Cox regression tests and, therefore, not affected by patient withdrawals (as 
they will be censored) provided that dropping out is unrelated to prognosis. Patients with missing 
information in other outcomes, such as clinical benefit rate or overall response, will be considered 
as no responders. Furthermore, we will report reasons for withdrawal for each randomization 
group and compare the reasons qualitatively. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
52 of 67 
 
8.7. Scientific committee review 
A Steering Committee (SC) has been established for this study. Initially, it is composed of the 
investigators, the study medical scientist, the Scientific Global Coordinator and two physicians 
expert in radium-223 management.  
 
The SC will meet on demand to review, discuss and evaluate all of the gathered safety data. In 
case of any arising safety concern, these meetings can also be called at any time at request of a 
participating investigator. At these meetings, MedSIR and the participating investigators must 
reach a consensus on safety data. MedSIR will prepare minutes from these meetings and 
circulate them to each investigator for comment prior to finalization.  
 
The study site Investigators and MedSIR will review patient data at least every four months. Each 
study site Investigator will monitor patients data for serious toxicities on an ongoing basis.  
 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
53 of 67 
 
9. ETHICAL CONSIDERATIONS 
9.1. Regulatory and ethical compliance 
The study will be conducted and reported in accordance with the protocol, the International 
Conference on Harmonization (ICH) guidelines, the ethical principles laid down in the Declaration 
of Helsinki, European Clinical Trials Regulation (Regulation (EU) No. 536/2014), and any 
applicable regulatory requirement.  
9.2. EC 
The conduct of the study must be authorized by a duly constituted EC. Authorization is required 
for study protocol, protocol amendments, informed consent forms, patient information sheets, and 
promotional materials. 
Wherever necessary, the investigator and/or Sponsor should contact the EC to ensure that 
accurate and timely information is being provided at every phase of the study. 
The principal investigator and/or Sponsor are responsible for providing, when required, written 
summaries of the study status to the EC annually or more frequently, in accordance with the 
requirements, policies and procedures set out by the EC. The investigators are also responsible 
for immediately informing the EC of any protocol amendment. 
In addition to reporting the AEs defined in the protocol to the Sponsor, the investigators must 
immediately reportany unexpected issues that entail a risk to patients to their respective ECs. 
Some ECs may request immediate reporting of all SAEs, while others may only require reporting 
of events if they are serious, related to the study treatment or unexpected. The Sponsor may 
provide the investigators with written safety reports or other safety-related reports. Safety reports 
should be made available to the EC for review and processing in accordance with the regulatory 
requirements and policies and procedures established by the EC and kept on file at the study site. 
9.3. Informed consent 
Before any protocol-related activity, the signed informed consent should be obtained from each 
patient. As part of this procedure, the study site investigator or his/her representative should 
explain verbally and in writing, the nature, duration and purpose of the study, as well as the action 
of the drugs so that the patient is aware of the possible risks, discomfort and adverse effects that 
may occur. Study patients will be informed of their right to withdraw from the study at any time 
and without any reason. The patient will receive all the information required by local regulations 
and ICH guidelines. 
Consent forms must be signed and dated by the patient or their authorized legal representative 
before starting their participation in the study. Each patient’s medical history or medical records 
should include an entry detailing the process of obtaining informed consent and that it was 
obtained in writing before the patient’s participation in the study. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
54 of 67 
 
One copy of the signed consent form should be provided to the patient or the patient’s authorized 
legal representative. 
Signed and dated consent forms should be kept in each patient’s study file. They should be made 
available to study monitors who may request them for review at any time. 
Consent forms should be reviewed whenever changes have been made to the procedures 
described in the informed consent or when new information becomes available that may affect 
the patient’s willingness to participate. 
In case of review or update of consent forms, each patient’s medical historyshould include an 
entry detailing the process of obtaining informed consent and that it was obtained in writing using 
the updated/reviewed consent form in order to continue their participation in the study. The final 
informed consent form approved by the EC should be provided to the Sponsor for regulatory 
purposes. 
9.4. Data protection 
The Sponsor will ensure confidentiality of the patient’s medical information, in accordance with 
the applicable laws and regulations. 
The study Sponsor, as data controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of such data 
confirms herewith compliance with Regulation (EU) 2016/679 of the European Parliament and of 
the Council, of 27 April 2016, on the protection of natural persons with regard to the processing 
of personal data and on the free movement of such data in all stages of data management. 
The data generated by this study will be made available to the representatives of national and 
local Health Authorities, Sponsor monitors, Sponsor representatives, and partners, as well as the 
EC of each study site for review, as needed. 
10. ORIGINAL DOCUMENTS, STUDY MONITORING AND QUALITY ASSURANCE 
10.1. 
Source data record 
Source data refers to all the information found in source files and certified copies of source files 
containing clinical findings, observations, or other activities that are part of the clinical study and 
which are necessary for study reconstruction and assessment. Source data is contained in source 
documents (comprising source documents and certified copies). 
Source documents are original documents, data, and records (e.g., hospital records, medical 
histories and office records, laboratory notes, memoranda, patients' diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, patients files, and records kept at 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
55 of 67 
 
the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
study). 
The Sponsor’s quality assurance group may assist in determining whether electronic records 
generated using computerized medical record systems used at investigational sites can be 
considered source documentation for the purposes of this protocol. 
If the site computerized medical record system has not been adequately validated for the 
purposes of clinical research (instead of general clinical practice), all paper source documentation 
should be kept on file to ensure that important protocol data entered on the CRFs can be verified. 
At a minimum, source documentation must be available to substantiate patient identification, 
eligibility, and participation; proper informed consent procedures; dates of visits; adherence to 
protocol procedures; adequate reporting and follow-up of AEs; administration of concomitant 
medication; study drug receipt/dispensing/return records; study drug administration information; 
and date of completion and reason. 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original documents, laboratory reports, medical records) in order to ensure data 
completeness and accuracy as required by study protocol. The investigator and/or site staff must 
make CRFs and source documents of patients enrolled in this study available for inspection by 
Sponsor or its representative at the time of each monitoring visit. 
The source documents must also be available for inspection, verification, and copying, as required 
by regulations, officials of the regulatory Health Authorities [e.g., US Food and Drug 
Administration(FDA), EMA, and others], and/or ECs. The study investigator and site staff must 
comply with applicable privacy, data protection, and medical confidentiality laws for use and 
disclosure of information related to the study and enrolled patients. 
The patient must also allow access to the patient's medical record. Each patient should be 
informed of this requirement prior to study start. 
10.2. 
Study monitoring and source data verification 
Sponsor or its representative will monitor study progress as frequently as necessary to ensure: 
- 
Protection of study patients’ rights and well-being. 
- 
Study data are accurate, complete, and verifiable from the source documents. 
- 
Conduct of the trial is in compliance with the approved protocol/amendment, good clinical 
practices (GCP), and applicable regulatory requirements. 
Study staff contact details are included in a document located on the investigator site file  
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original documents, laboratory reports, medical records, patients’ diaries) in order to 
ensure data completeness and accuracy as required by study protocol. The investigator and/or 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
56 of 67 
 
site staff must make CRFs and source documents of patients enrolled in this study available for 
inspection by the Sponsor or its representative at the time of each monitoring visit. 
10.3. 
Record retention 
Investigators should retain all study records in a secure place with restricted access as per 
applicable regulatory requirements. The investigator must consult a Sponsor representative 
before disposal of any study records and must notify the Sponsor (of any change in the location, 
disposition, or custody of the study files. 
Essential documents must be retained by the investigator for at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least two years have elapsed since 
the formal discontinuation of clinical development of the investigational product. “Essential 
documents” are defined as those documents which individually and collectively allow for the 
assessment of the conduct of the study and the quality of the resulting data. These documents 
must be retained for a longer period if required by the applicable regulatory requirements or as a 
result of an agreement with the Sponsor. It is the Sponsor’s responsibility to notify the investigator 
or site when these documents are no longer needed(ICH E6 Guidelines, 4.9.5). 
The study site investigator should not dispose of records belonging to this study without first (1) 
obtaining written approval from the Sponsor (2) offering the Sponsor an opportunity to collect 
these records. The study site investigator will be responsible for retaining suitable and accurate 
electronic or paper copies of source documentation containing observations and data collected 
from this study.  
10.4. 
Data quality assurance 
During the study or upon its completion, the quality assurance auditor(s) designated by Sponsor 
or the competent authorities may wish to perform an audit of the sites. Investigators are expected 
to cooperate in these audits, offering their assistance, and providing auditors with the 
documentation they require (including source documents). 
The Sponsor’s representatives are responsible for contacting and visiting the investigator in order 
to inspect the facilities and, upon request, to inspect clinical trial records (e.g., CRF and other 
pertinent data), provided that patient confidentiality is respected. 
The investigator agrees to cooperate with the monitor to ensure that all issues detected 
duringthese monitoring visits are resolved, including delays in completing CRFs. 
In accordance with the ICH E6 Guideline for GCP and the Sponsor’s audit plans, the Sponsor’s 
Department of Quality Assurance or its representatives may perform an audit of this study. An 
inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
57 of 67 
 
related records will be carried out in order to assess the conduct of the study and compliance with 
the protocol, the ICH guidelines for GCP (ICH E6), and relevant regulatory requirements. 
11. DATA MANAGEMENT 
11.1. 
Data entry and processing 
In this study, the investigator and/or site staff will regularly enter all data into the CRFs. 
The investigator must review all data included in the CRF to ensure its accuracy. 
Reconciliation of the data will be performed by the designated CRO. At the end of the study, any 
protocol non-compliances will be identified and recorded as part of the clinical database. Once all 
of these tasks are complete and the accuracy and completeness of the database has been 
verified, it will be locked and the data will become available for data statistical analysis. 
11.2. 
Data clarification 
As part of the conduct of the trial, Sponsor may have questions about the data entered by the 
site, referred to as queries. The monitors and the Sponsor are the only parties that can generate 
a query. 
11.3. 
Data coding procedures 
Coding of AEs, medical history, and prior and concomitant medications will be performed using 
standard dictionaries described in the data management plan. 
12. STUDY MANAGEMENT 
12.1. 
Study discontinuation 
MedSIR reserves the right to discontinue the study at any time for safety or administrative 
reasons. If the study is discontinued and/or the site is closed for any reason, all of the 
investigational study drugs can be destroyed locally at the site according local law regarding 
radioactive products) . All of the actions needed to assess or maintain study patient safety will 
continue as required, despite study discontinuation. 
12.2. 
Protocol amendments 
Any change or addition to the protocol requires a written protocol amendment or administrative 
letter that must be approved by Sponsor, the global scientific coordinator, the study site 
investigator, and the EC/Health Authorities when applicable. This requirement should not, under 
any circumstances, prevent any immediate action taken by the study site investigator or Sponsor 
to ensure the safety of all the patients enrolled in the study. If, in the opinion of the study site 
investigator, an immediate protocol amendment is required and it is applied for safety reasons, 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
58 of 67 
 
this process should be reported to Sponsor as soon as possible (within 24hours) and the EC will 
be informed, as needed. 
12.3. 
Publication policy and protection of trade secrets 
All of the data generated by this study should be considered highly confidential and should not be 
disclosed to persons who are not directly related to the study without prior written permission from 
the global scientific coordinator and Sponsor. Nevertheless, full access is granted to authorized 
officials of Health Authorities, the global scientific coordinator or study site investigator, and 
Sponsor staff (or their representatives) for record inspection and copying. All of the investigational 
products, patient body fluids and/or other collected materials will only be used in accordance with 
this protocol, unless otherwise agreed in writing between the global scientific coordinator or study 
site investigator and Sponsor. 
The Sponsor will ensure that, as far as possible, the study results are published in the form of 
scientific/clinical articles in prestigious scientific peer-reviewed journals. These documents will be 
prepared with the full participation of the principal investigators and in accordance with applicable 
guidelines for good publication practice and with international recommendations, such as those 
from the International Committee of Medical Journal Editors (ICMJE) and all elements of the 
Consort Statement (2010). 
The Sponsor will be notified of any attempt to publish data obtained during the study and 
permission to do so must first be obtained from the Sponsor before publication. 
12.4. 
Insurance 
The Sponsor contracts an insurance policy to cover the responsibilities of the investigator and 
other parties participating in the study, according to the applicable Spanish legislation. 
• 
Insurance company:  CHUBB Insurance Company of Europe SE. c/ José Abascal, nº56, 
5a planta, 28003 Madrid (Spain). 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
59 of 67 
 
13. REFERENCES 
1. 
Horwich, A., et al., Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, 
treatment and follow-up. Ann Oncol, 2013. 24 Suppl 6: p. vi106-14. 
2. 
https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. 
3. 
Cassinello, J., et al., SEOM clinical guidelines for the treatment of metastatic prostate 
cancer. Clin Transl Oncol, 2014. 16(12): p. 1060-6. 
4. 
Sweeney, C.J., et al., Chemohormonal Therapy in Metastatic Hormone-Sensitive 
Prostate Cancer. N Engl J Med, 2015. 373(8): p. 737-46. 
5. 
Gravis, G., et al., Androgen-deprivation therapy alone or with docetaxel in non-castrate 
metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet 
Oncol, 2013. 14(2): p. 149-58. 
6. 
Scher, H.I., et al., Increased survival with enzalutamide in prostate cancer after 
chemotherapy. N Engl J Med, 2012. 367(13): p. 1187-97. 
7. 
Beer, T.M., et al., Enzalutamide in metastatic prostate cancer before chemotherapy. N 
Engl J Med, 2014. 371(5): p. 424-33. 
8. 
de Bono, J.S., et al., Abiraterone and increased survival in metastatic prostate cancer. N 
Engl J Med, 2011. 364(21): p. 1995-2005. 
9. 
Ryan, C.J., et al., Abiraterone in metastatic prostate cancer without previous 
chemotherapy. N Engl J Med, 2013. 368(2): p. 138-48. 
10. 
Kantoff, P.W., et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer. 
N Engl J Med, 2010. 363(5): p. 411-22. 
11. 
de Bono, J.S., et al., Prednisone plus cabazitaxel or mitoxantrone for metastatic 
castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-
label trial. Lancet, 2010. 376(9747): p. 1147-54. 
12. 
Lebdai, S., et al., What do we know about treatment sequencing of abiraterone, 
enzalutamide, and chemotherapy in metastatic castration-resistant prostate cancer? World J Urol, 
2016. 34(5): p. 617-24. 
13. 
Shirley, M. and P.L. McCormack, Radium-223 dichloride: a review of its use in patients 
with castration-resistant prostate cancer with symptomatic bone metastases. Drugs, 2014. 74(5): 
p. 579-86. 
14. 
Nilsson, S., et al., First clinical experience with alpha-emitting radium-223 in the treatment 
of skeletal metastases. Clin Cancer Res, 2005. 11(12): p. 4451-9. 
15. 
Nilsson, S., et al., Bone-targeted radium-223 in symptomatic, hormone-refractory 
prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol, 
2007. 8(7): p. 587-94. 
16. 
Parker, C., et al., Alpha emitter radium-223 and survival in metastatic prostate cancer. N 
Engl J Med, 2013. 369(3): p. 213-23. 
17. 
Dehm, S.M. and D.J. Tindall, Androgen receptor structural and functional elements: role 
and regulation in prostate cancer. Mol Endocrinol, 2007. 21(12): p. 2855-63. 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th Jan 2020 
Version 4 
60 of 67 
 
18. 
Brooke, G.N. and C.L. Bevan, The role of androgen receptor mutations in prostate cancer 
progression. Curr Genomics, 2009. 10(1): p. 18-25. 
19. 
Antonarakis, E.S., et al., AR-V7 and resistance to enzalutamide and abiraterone in 
prostate cancer. N Engl J Med, 2014. 371(11): p. 1028-38. 
20. 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, 
U.S.D.o.H.a.H. Services, Editor 2010, National Institues of Health, National Cancer Center. 
21. 
Scher, H.I., et al., Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer 
Clinical Trials Working Group. J Clin Oncol, 2008. 26(7): p. 1148-59. 
22. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
23. Jones D, Mitchell I, Hillman K, Story D. Defining clinical deterioration. Resuscitation. 2013 
Aug;84(8):1029-34. 
24. 
https://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. 
25. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. 
26. 
Kwak, M. and S.H. Jung, Phase II clinical trials with time-to-event endpoints: optimal two-
stage designs with one-sample log-rank test. Stat Med, 2014. 33(12): p. 2004-16. 
27.      Jung S-H (2013) Randomized phase II cancer clinical trials. Boca Raton, FL: Taylor and 
Francis Group. 
28. 
Petrylak, D.P., et al., Docetaxel and estramustine compared with mitoxantrone and 
prednisone for advanced refractory prostate cancer. N Engl J Med, 2004. 351(15): p. 1513-20. 
 
 
 


 
  
 
 
 
EudraCT No.: 2016-001888-36 
 
  
 
 
 
       Protocol No.: MedOPP098 
 
 
  
 
                     Protocol Date: 30th January 2020 
 
 
                                                                                            Version 4 
 
61 of 67 
 
Appendix 1: Schedule of study assessments and procedures 
 
Study Period 
Screening Treatment period 
Follow-up period 
Day 
-28 to -1 
Each cycle* 
(every 28 days) 
End 
of 
treatment ** 
 
Every 3 months 
(Efficacy FUP)12  
  At time of DP**  EoS (Safety FUP) 13 
Informed Consent1 
X 
 
 
 
 
 
Baseline 
signs/symptoms  
X 
X 
X 
X 
X 
 
Check 
of 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
Brief 
pain 
inventory 
(short form) (BPI-SF) 
X 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
X 
Physical 
Examination 
and ECOG status3,4 
 
X 
 
X 
 
X 
 
X 
 
X 
 


 
  
 
 
 
EudraCT No.: 2016-001888-36 
 
  
 
 
 
       Protocol No.: MedOPP098 
 
 
  
 
                     Protocol Date: 30th January 2020 
 
 
                                                                                            Version 4 
 
62 of 67 
 
Study Period 
Screening Treatment period 
Follow-up period 
Day 
-28 to -1 
Each cycle* 
(every 28 days) 
End 
of 
treatment ** 
 
Every 3 months 
(Efficacy FUP)12  
  At time of DP**  EoS (Safety FUP) 13 
Concomitant Medication 
Reporting5 
X 
X 
 
X 
 
X 
X 
 
Health-related quality of 
life 
(HRQoL) 
questionnaire6 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
AE reporting7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
                  X  
Radiological 
Tumor 
Assessments8 
X 
every 3 cycles 
 
X 
 
X 
X 
 
Standard Laboratory Procedures 
Hematology9,^ 
X 
X 
X 
X 
X 
 
Biochemistry10, ^ 
X 
X 
X 
X 
X 
 
PSA determination^ 
 
X 
 
X 
 
X 
 
X 
 
X 
 


 
  
 
 
 
EudraCT No.: 2016-001888-36 
 
  
 
 
 
       Protocol No.: MedOPP098 
 
 
  
 
                     Protocol Date: 30th January 2020 
 
 
                                                                                            Version 4 
 
63 of 67 
 
Study Period 
Screening Treatment period 
Follow-up period 
Day 
-28 to -1 
Each cycle* 
(every 28 days) 
End 
of 
treatment ** 
 
Every 3 months 
(Efficacy FUP)12  
  At time of DP**  EoS (Safety FUP) 13 
Testosterone 
determination^ 
X 
 
 
 
 
 
Treatment Administration 
Radium-223 at dose of 
55 
kBq/Kg 
one 
IV 
injection 
 
D1 (for a total of 
six IV injections) 
 
 
 
 
 
 
Research Central Laboratory Procedures 
Blood sample collection 
(split 
variant 
AR-V7 
determination)11 
 
X 
 
 
 
X 
 
 
X 
 
Blood sample collection 
(CTC count)11 
X 
 
X 
 
X 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th January 2020 
Version 4 
 
64 of 67 
 
* 
All visits must occur within ± 7 working days from the scheduled date. 
** 
If disease progression coincides with the end of treatment visit, the evaluations planned for both visits will 
coincide, they will only be performed once (including blood sample for central laboratory). 
 
^ 
Local laboratory tests scheduled for day 1 of all cycles must be performed within 72 hours prior toconfirm to the 
patient if treatment can be followed up. 
1. 
Signed written informed consent obtained prior to any trial-specific procedure. 
2. 
Complete medical history and demographics (including age, gender, and ethnic origin) and all medications 
taken the last 28 days prior to enrollment will be collected.  
3. 
Physical examination and vital signs (including respiratory rate, blood pressure measurements, heart rate, and 
body temperature) and weight measurement will be performed prior to enrollment.  
4. 
ECOG performance status will be assessed before trial drug adminstration and before the administration of 
each cycle.  
5. 
Relevant concomitant medication will be recorded at screening and on an ongoing basis. 
6. 
FACT-P, Version 04 
7. 
All AEs occurring during the trial and until the treatment discontinuation visit (end of study visit) have to be 
recorded with grading according to NCI-CTCAE version 4.0. 
8. 
Baseline assessments of the torax, abdomen, and pelvis (preferably CT or MRI in case of contrast allergy) must 
be performed no more than 28 days before the first trial treatment. Baseline bone scan must be performed no 
more than 28 days before the first trial treatment. Post-baseline assessments have to be performed every 12 
weeks ± 7 working days after the first dose using the same imaging method and where possible obtained at the 
same institution for an individual patient as used during screening until progression disease. Radiographic bone 
progression will require the persistence of new lesions on a confirmatory scan at least six weeks later. In those 
patients who receive 6 treatment cycles, the radiological tumour assessment corresponding to week 24 will be 
performed for the EOT visit. 
9. 
Hematological test will be performed as per local standard of care and clinical indication before treatment 
administration. These values should be included: hemoglobin, hematocrit, red blood cell count, platelet count, 
and white blood cell count with differential count (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils). 
10. Biochemistry test will be performed as per local standard of care and clinical indication before first treatment 
administration and first day of follow-up. These values should be included: coagulation, chemistry with renal 
function analysis (serum creatinine, creatinine clearance according to the Cockroft-Gault formula), liver function 
(AST, ALT, ALP, direct and total bilirubin), glucose, sodium, potassium, calcium, chloride, magnesium, uric acid, 
total protein, albumin, and lactate dehydrogenase. 
11. Blood sample for central laboratory prior to the start of study treatment, at the end of treatment and at time to 
documented progression disease (if the patient ends treatment due to progressive disease, only one blood 
sample will be sent at this point). 
12. After end of treatment (if no progressive disease documented), efficacy follow-up visits will be performed every 
3 months including radiological tumour assessments until disease progression.  
13. After disease progression, a safety follow-up visit will be performed within three following months and 24 months 
after last dose of treatment to evaluate symptomatic skeletal related events, overall survival and post-study 
anticancer therapy. 
 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th January 2020 
Version 4 
 
65 of 67 
 
Appendix 2: Response Evaluation Criteria in Solid Tumors Guidelines (RECIST criteria) 
(version 1.1) 
 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
 
Appendix 3: Instructions for blood sample collection. Detection of CTCs 
 
CTC analysis will be conducted using high definition system to identify CTCs(HD-CTCs). It is 
distinct in that it does not rely on any single protein enrichment strategies. Instead, all nucleated 
cells are retained and immunofluorescently stained with monoclonal antibodies targeting 
cytokeratin (CK), an intermediate filament found exclusively in epithelial cells, a pan leukocyte 
specific antibody targeting CD45, and a nuclear stain, DAPI. All nucleated blood cells are imaged 
in multiple fluorescent channels to produce high quality and high resolution digital images that 
retain fine cytologic details of nuclear contour and cytoplasmic distribution. This enrichment-free 
strategy results in high sensitivity and high specificity, while adding high definition cytomorphology 
to enable detailed morphologic characterization of a CTC population known to be heterogeneous. 
A key advantage of this approach is that multiple analysis parameters can be pursued to identify 
and characterize specific populations of interest. 
 
Blood samples (10 mL) will be collected using standard streck cell-free DNA BCT by venipuncture. 
The first 5 ml of blood collected from the fresh venipuncture cannot be used for the collection into 
de Streck tubes due to possibility of contaminating epithelial cells during venipuncture. These 
samples will be stored at room temperature and ship on day of collection in shipper at ambient 
temperature (date and time of draw are required) to Covance Central Laboratory Services 
(Switzerland) and they will be received and processed within 24 hours. 
 
Blood sample processing for HD-CTC detection 
Blood specimens will be rocked for five minutes before a WBC will be measured using the 
Hemocue white blood cell system (HemoCue, Sweden). Based upon the WBC count, a volume 
of blood will be subjected to erythrocyte lysis (ammonium chloride solution). After centrifugation, 
nucleated cells will be re-suspended in PBS and attached as a monolayer on custom made glass 
slides. The glass slides will be the same size as standard microscopy slides but have a proprietary 
coating that allows maximal retention of live cells.  
Each slide can hold approximately three million nucleated cells, thus the number of cells plated 
per slide depend on the patients WBC. For HD-CTC detection, four slides will be used as a test. 
The remaining slides created for each patient will be stored at −80°C for future experiments.  


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th January 2020 
Version 4 
 
66 of 67 
 
Four slides will be thawed from each patient, then cells will be fixed with 2% paraformaldehyde, 
permeabilized with cold methanol, and non-specific binding sites will be blocked with goat serum. 
Slides will be subsequently incubated with monoclonal anti-pan CK antibody (Sigma) and CD45-
Alexa 647 (Serotec) for 40 minutes at 37°C. After PBS washes, slides will be incubated with Alexa 
Fluor 555 goat anti-mouse antibody (Invitrogen) for 20 minutes at 37°C. Cells will be 
counterstained with DAPI for 10 minutes and mounted with an aqueous mounting media. 
 
Detection of AR-V7 in CTCs  
mRNA expression analyses will be performed using the ProstateCancerDetect kit with 
multiplexed reverse-transcription polymerase-chain-reaction (qRT-PCR) primers to detect the 
presence of CTCs, and custom primers designed to detect the full-length-AR (AR-FL) and AR 
AR-V7. The relative AR-V7 transcript abundance will be determined by calculating the ratio of 
AR-V7 to AR-FL.  
 
Details will be provided in the study laboratory manual. All samples will be labelled with patient 
study number, date and time of collection. 
 
 


 
EudraCT No.: 2016-001888-36 
 
Protocol No.: MedOPP098 
 
 
Protocol Date: 30th January 2020 
Version 4 
 
67 of 67 
 
Appendix 4: Principal investigators 

SAP_001.pdf: