Clinical Trials Register

Summary
EudraCT Number:	2013-004879-13
Sponsor's Protocol Code Number:	UKF2013/12
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-28
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2013-004879-13

A.3

Full title of the trial

α-RT; Phase II open-label study to evaluate the efficacy and safety of
Radium-223 dichloride in combination with external beam radiotherapy (EBRT) vs.
EBRT alone in the treatment of advanced castration resistant prostate
carcinoma with limited bone metastases

α-RT; offene Phase II Studie zur Evaluierung der Effizienz und Sicherheit von Radium-223 Dichlorid in Kombination mit perkutaner Strahlentherapie vs. alleiniger perkutaner Strahlentherapie bei der Behandlung von fortgeschrittenen kastrationsresistenten Prostatakarzinomen mit einer limitieren Anzahl an Knochenmetastasen. (α-RT)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

α-RT; offene Phase II Studie zur Untersuchung der Wirksamkeit und Sicherheit von Radium-223 Dichlorid. Untersucht wird die alleinige Gabe von Radium-223 Dichlorid im Vergleich zur Gabe des Medikamentes gemeinsam mit einer Strahlentherapie. Behandelt werden Patienten mit mind. einer bis höchstens fünf Knochenmetastasen durch Prostatakrebs, falls eine Hormontherapie nicht mehr wirkt.

A.3.2

Name or abbreviated title of the trial where available

α-RT

A.4.1

Sponsor's protocol code number

UKF2013/12

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Universitätsklinikum Freiburg
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bayer Vital GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinik Freiburg
B.5.2	Functional name of contact point	Studienbüro
B.5.3	Address:
B.5.3.1	Street Address	Robert-Koch-Str. 3
B.5.3.2	Town/ city	Freiburg
B.5.3.3	Post code	79106
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 761270 94630
B.5.5	Fax number	+49761270 95110

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Xofigo® (Radium 223 dichloride)
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Vital GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Intravenous bolus use (Noncurrent)
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	Yes
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Bone metastases in advanced castration resistant prostate carcinoma.

Knochenmetastasen bei fortgeschrittenem kastrationsresistenten Prostatakarzinom

E.1.1.1

Medical condition in easily understood language

Bone metastases in prostate carcinoma, if antihormone therapy is no longer efficient

Knochenmetastasen bei fortgeschrittenem Prostatakarzinom und Versagen der Hormontherapie

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	PT
E.1.2	Classification code	10036909
E.1.2	Term	Prostate cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10005993
E.1.2	Term	Bone metastases
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	PT
E.1.2	Classification code	10062904
E.1.2	Term	Hormone-refractory prostate cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Radiological progression-free survival (rPFS) defined as time from randomization to radiological progression or death

Das radiologische progressionsfreie Überleben, definiert als Zeitraum von der Randomisation bis zum radiologischen Progress oder bis zum Tod

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Translational research Project:
Molecular markers in patients with CRPC and oligometastatic bone disease
The goal of this sub-project is to identify and validate novel molecular biomarkers, in this case miRNA, in urine and blood that correlate with clinical outcome and can therefore be used as prognostic and/or predictive markers in addition to the existing risk-stratifying parameters. This may improve clinical decision making by identifying patients who benefit from different treatment strategies based on molecular characteristics.
Immunomonitoring
There are potential changes in immune system induced by cytotoxic side effect of radiotherapy and Radium-223 or radiotherapy alone, that shall be investigated.
Determination of leukocyte counts and characterization of leukocyte subsets (in particular the lymphocyte subsets) will be performed by multicolor flow cytometry prior to EBRTduring follow up.
The acquisition of data and collection of material for all projects are planned to be multicentric. The analysis will take place in Freiburg, partially together with other academic cooperation partners.
Quality of life – additional research
As compared to the designated standard quality of life questionnaires used in the main study, this project aims at validating QoL scales that are easier to use in clinical practice (e.g. verbal rating scale VRS5, single item score).
Magnet resonance imaging
In this sub-project, volunteering patients will undergo additional MRI examinations measuring the lesion volume as a function of time and its correlation of the functional parameters like perfusion, diffusion, and T2*. Aditionally, non-responding lesion sub-volumes will be monitored.
These sub-projects will be further specified in respective protocols and only be performed provided separate IEC approval is available.

E.3

Principal inclusion criteria

Eligible patients will conform to all of the inclusion criteria listed below:

1. Has provided written informed consent. Subjects must be able to understand and be willing to sign the written informed consent form (ICF). A signed ICF must be appropriately obtained prior to the conduct of the any trial- specific procedure. Enrollment (entry) in the study is defined as the signing of the informed consent.
2. Age ≥ 18 and ≤ 85 years
3. Patients with progressive castration resistant prostate cancer (CRPC) with 1-5 bone metastases for whom Radium-223 dichloride constitutes first-line cytostatic treatment
4. Primary tumor (and its local recurrence, if applicable) controlled by effective local treatment
5. If diagnosed, pelvic lymph node metastases controlled by effective local treatment
6. At least 1 not previously locally treated skeletal metastasis on bone scan without non-bone distant metastases (e.g. lung, liver, and/or brain metastases) and without pathologically enlarged lymph nodes above the pelvis
7. Progressive disease is defined either by:
- The appearance of new bone lesions. If progression is based on new lesion(s) on bone scan only without an increase in prostate specific antigen (PSA), PSA values from 3 assessments within the last 6 months must be provided; OR
- In the absence of new bone lesions by 2 consecutive increases in serum PSA over previous reference value, which should not be more than 6 months before screening, each measured at least 1 week apart with the last PSA ≥5 ng/mL
8. Life expectancy of at least 6 months
9. Zubrod (WHO/ECOG) Performance Status (PS) 0 or 1
10. Adequate bone marrow, liver and renal function as assessed by the following laboratory
requirements to be conducted within 7 days prior to start of therapy:
- Hemoglobin > 10.0 g/dl
- Absolute neutrophil count (ANC) >1,500/µl
- Platelet count >100,000/μl
- Total bilirubin < 1.5 times the institutional upper limit of normal (ULN)
- ALT and AST < 2.5 x institutional upper limit of normal (ULN)
- Serum creatinine < 2 x upper limit of normal.
11. Patient has or has had symptoms (e. g. pain or micro-fractions) from bone metastases

E.4

Principal exclusion criteria

Excluded medical conditions:

1. More than 5 not previously locally treated bone metastases as diagnosed by bone scintigraphy;
2. Visceral or lymph node metastases above the pelvis as assessed by computed tomography (CT) (or other imaging modality)
3. History of HIV infection or chronic hepatitis B or C
4. Active clinically serious infections (> grade 2 NCI-CTC version 4.03)
5. History of organ allograft
6. Patients undergoing renal dialysis
7. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study if not in complete remission for at least 5 years since date of diagnosis, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry.
8. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
9. Imminent or history of spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI)
10. Any other serious illness or medical condition, such as but not limited to:
- Cardiac failure New York Heart Association (NYHA) III or IV
- Crohn’s disease or ulcerative colitis
- Bone marrow dysplasia
11. Fecal incontinence
12. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
13. Known allergy to Radium-223 dichloride (i.e. to active substance or one of the constituents)

Excluded therapies and medications, previous and concomitant:

1. Anticancer chemo- or targeted therapy for CRPC (e.g. docetaxel or cabazitaxel)
2. Local relapse in previously irradiated osseous metastases
3. Major surgery within 4 weeks of study entry.
4. Systemic therapy with radionuclides (e.g., strontium-89, samarium-153,
rhenium-186, or rhenium-188, or radium-223 dichloride) for the treatment of bone metastases
5. Autologous bone marrow transplant or stem cell rescue within 4 months of study entry
6. Use of biologic response modifiers, such as G-CSF, within 3 week of study entry. [G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator; however they may not be substituted for a required dose reduction.] [Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study entry or during the study]
7. Investigational drug therapy outside of this trial during or within 4 weeks of study entry

E.5 End points

E.5.1

Primary end point(s)

Time to radiological progression-free survival defined as time from randomization to radiological progression according to the “Recommendations of the Prostate Cancer Clinical Trials Working Group” published by Scher et al. (JCO 2008) (based on new lesions in bone scan and CT /MRI or death)

E.5.1.1

Timepoint(s) of evaluation of this end point

Intent-to-treat analysis at the end of study.

E.5.2

Secondary end point(s)

1. Overall survival
2. Time to local progression in any of the EBRT treated bone metastases of CRT vs. HIRT treatment techniques
3. Time to distant bone metastasis progression outside the RT target volumes
4. Time to SRE (using the same criteria as in ALSYMPCA)
5. Pain control (weekly visual analog score and “Brief pain inventory short form”)
6. Disease Control Rate (DCR); Response rates (CR, PR, SD according to RECIST criteria)
7. PSA response, time to PSA response and time to PSA normalization
8. Bone ALP response, time to bone ALP response

Explorative:
- One year bone progression free survival
- Health-related Quality of Life (PAL15 + BM22)
- Biomarker program using blood samples to be defined by a separate protocol in more detail.
- Safety and tolerability
- Time to opiate use for cancer pain defined as the interval from the date of randomization to the date of opiate use.
- Time to pain progression defined as the interval from randomization to the first date a subject experiences a BPI-SF increase by ≥30% and at least 2 points from baseline in the worst pain index score (WPS) observed at 2 consecutive evaluations ≥4 weeks apart without decrease in analgesic usage score.
- Local symptomatic treatment failure (LSTF) defined as the time from randomization to the occurrence of one of the following:
Development, increase or recurrence of tumor related symptoms at irradiated bone metastases with
- Increase of local symptoms by one grade according to NCI-AE v4.03 or
- Recurrence of local symptoms to the same grade according to NCI-AE v4.03 as assessed at randomization or
- Development of new local symptoms of any grade according to NCI-AE v4.03

- Local treatment failure (LTF) defined as the time from randomization to the occurrence of one of the following:
- Local SSE-FS at irradiated bone metastases
- Evidence of radiological progression measured according to methodology from RECIST v1.1 (the longest diameter including the osteoblastic part will be used: this diameter has to be doubled to be counted as recurrence and only an increase above the longest diameter at inclusion will be counted as recurrence)

E.5.2.1

Timepoint(s) of evaluation of this end point

- In an interim analysis concerning safety after 15 patients included in each study arm.
- Intent-to-treat analysis at the end of study.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

lack of treatment

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

137

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

137

F.2 Gender

F.2.1

Female

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

140

F.4.2

For a multinational trial

F.4.2.1

In the EEA

274

F.4.2.2

In the whole clinical trial

274

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After active assessment follow-up period, patients will be followed up until death.
Follow up will be in accordance to applicable clinical guidelines and best standard of care.
No special study specific therapy will be administered during the follow-up time.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-11-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-05-30

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