Clinical Trial Results:
A re-treatment safety study of radium-223 dichloride in subjects with castration-resistant prostate cancer with bone metastases who received an initial course of six doses of radium-223 dichloride 50 kBq/kg every four weeks
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Summary
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EudraCT number |
2013-003046-17 |
Trial protocol |
SE NO FI IT ES GB DE |
Global end of trial date |
12 Apr 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Mar 2018
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First version publication date |
12 Mar 2018
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BAY88-8223/16506
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01934790 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
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Public contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Apr 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Apr 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the safety of re-treatment with up to 6 doses of radium-223 dichloride 50 kBq/kg given every 4 weeks in subjects with castration-resistant prostate cancer (CRPC) with bone metastases who received an initial course of 6 doses of radium-223 dichloride 50 kBq/kg.
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Protection of trial subjects |
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Only after the subject voluntarily signed the informed consent form was he/she able to enter the study. If the subject was not capable of providing a signature, an oral statement of consent could have been given in the presence of a witness. Each subject was assured of the right to withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Dec 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
7 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Norway: 4
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Country: Number of subjects enrolled |
Spain: 5
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Country: Number of subjects enrolled |
Sweden: 3
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Country: Number of subjects enrolled |
Finland: 1
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Country: Number of subjects enrolled |
Italy: 3
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Country: Number of subjects enrolled |
Israel: 7
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Country: Number of subjects enrolled |
United States: 21
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Worldwide total number of subjects |
44
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EEA total number of subjects |
16
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
13
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From 65 to 84 years |
26
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85 years and over |
5
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Recruitment
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Recruitment details |
Overall, 59 subjects were enrolled into the study centers in 7 countries worldwide, from 22-Dec-2013 (first patient first visit) to 12-Apr-2017 (last patient last visit). | ||||||||||||||||||||
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Pre-assignment
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Screening details |
The study was conducted at 16 study centers that screened 59 subjects. Of them, 14 were screening failures and the remaining 45 subjects were assigned to treatment. | ||||||||||||||||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
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Arms
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Arm title
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Radium-223 dichloride (Xofigo, BAY88-8223) | ||||||||||||||||||||
Arm description |
Subjects received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Radium-223 dichloride
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Investigational medicinal product code |
BAY88-8223
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Due to database constraint, number of subjects entering each study phase was reported as milestones. |
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Baseline characteristics reporting groups
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Reporting group title |
Radium-223 dichloride (Xofigo, BAY88-8223)
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Reporting group description |
Subjects received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Radium-223 dichloride (Xofigo, BAY88-8223)
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Reporting group description |
Subjects received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections. | ||
Subject analysis set title |
Safety Analysis Set (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who received at least one dose of study drug
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Subject analysis set title |
Active Follow-up Analysis Set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who were reported in the End of Treatment (EOT) electronic case report form (eCRF) as planning to participate in the active follow-up.
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End point title |
Number of subjects with treatment-emergent adverse events (AEs) [1] | ||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. A treatment-emergent adverse events (TEAE) is defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of radium-223 dichloride.
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End point type |
Primary
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End point timeframe |
Up to 2.5 years
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [2] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with treatment-emergent serious adverse events (SAEs) [3] | ||||||||
End point description |
TESAE occurred after the start of radium-223 dichloride treatment until 30 days after the last dose and results in death; is life-threatening; requires inpatient hospitalization or prolongs existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly / birth defect; is another medically important serious event as judged by the investigator; or is an occurrence of leukemia, myelodysplastic syndrome, aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary malignancy, such as acute myeloid leukemia.
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End point type |
Primary
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End point timeframe |
Up to 2.5 years
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [4] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with Radium-223 dichloride-related AEs in the active follow-up period [5] | ||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study.
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End point type |
Primary
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End point timeframe |
Up to 2 years after last treatment
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [6] - Active Follow-up Analysis Set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with Radium-223 dichloride-related SAEs in the active follow-up period [7] | ||||||||
End point description |
Treatment-related SAE is any SAE that, according to the investigator’s causality assessment, is possibly or probably related to treatment with radium-223 dichloride.
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End point type |
Primary
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End point timeframe |
Up to 2 years after last treatment
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [8] - Active Follow-up Analysis Set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with high/low abnormalities in hematology variables at any visit after treatment start [9] | ||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Up to 2.5 years
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [10] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of subjects with high/low abnormalities in biochemistry variables at any visit after treatment start [11] | ||||||||||||||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Up to 2.5 years
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [12] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Number of subjects who discontinued Radium-223 dichloride treatment due to treatment emergent AEs or death [13] | ||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. A treatment-emergent adverse events (TEAE) is defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of radium-223 dichloride.
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End point type |
Primary
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End point timeframe |
Up to 2.5 years
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| Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [14] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Radiological progression free survival (rPFS) | ||||||||
End point description |
Radiological progression-free survival (rPFS) was defined as the time from the treatment start date to the date of radiological disease progression or death from any cause (if death occurred before such progression), as documented by the investigator. Subjects not experiencing death or radiological disease progression at the database cutoff for primary completion were censored at the last radiological disease progression assessment.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2 years after last treatment
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| Notes [15] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to radiological bone progression | ||||||||
End point description |
Time to radiological bone progression was defined as the time (days) from the treatment start date to the date of radiological bone progression (according to the adapted PCWG2 [Prostate Cancer Clinical Trials Working Group 2] criteria), as documented by the investigator. Subjects not experiencing radiological bone progression at the database cutoff for primary completion were censored at the last radiological bone progression assessment. An entry of ‘99999’ indicates that the value could not be estimated due to censored values.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2 years after last treatment
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| Notes [16] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of subjects with total alkaline phosphatase (ALP) response | ||||||||||||||
End point description |
Total alkaline phosphatase (ALP) response was defined as ≥ 30% reduction of the blood total ALP level compared with the baseline values. Total ALP response rate was defined as the number of subjects with total ALP response divided by the total number of subjects evaluable for total ALP response.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2.5 years
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| Notes [17] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Time to total ALP progression | ||||||||
End point description |
Total ALP progression was defined as a ≥ 25% increase above the nadir (lowest baseline or post-baseline) value to at least 1.5 x ULN (upper limit of normal). The time to total ALP progression was defined as the time (days) from the treatment start date to the date of first total ALP progression. Subjects not experiencing ALP progression at the database cutoff date, whether or not surviving, were censored at the last ALP laboratory assessment. An entry of ‘99999’ indicates that the value could not be estimated due to censored values.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2 years after last treatment
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| Notes [18] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percent change in total ALP | ||||||||||||
End point description |
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End point type |
Other pre-specified
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End point timeframe |
Baseline and Week 12, Week 24
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| Notes [19] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of subjects with prostate specific antigen (PSA) response | ||||||||||||||
End point description |
Prostate specific antigen (PSA) response was defined as a ≥ 30% reduction of blood PSA level compared with the baseline value, confirmed by a second subsequent PSA value with a ≥ 30% reduction from baseline approximately 4 or more weeks later. Prostate specific antigen response rate was defined as the number of subjects with PSA response divided by the total number of subjects evaluable for PSA response.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2.5 years
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| Notes [20] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Time to PSA progression | ||||||||
End point description |
Prostate specific antigen progression was defined as a ≥ 25% increase above the nadir (lowest baseline or post-baseline) value, and an increase in absolute value of ≥ 2 ng/mL above nadir. The time to PSA progression was defined as the time (days) from the treatment start date to the date of first PSA progression. Subjects without PSA progression as of the database cutoff for primary completion, whether or not surviving, were censored at the last PSA laboratory assessment.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2 years after last treatment
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| Notes [21] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall survival | ||||||||
End point description |
Overall survival (OS) was defined as the time (days) from the treatment start date to the date of death due to any cause. For subjects who were still alive or who were lost to follow-up as of the database cutoff date for the primary completion, OS was censored at the last known alive date on or prior to the database cutoff date.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2 years after last treatment
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| Notes [22] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of subjects with pain improvement | ||||||||||||||
End point description |
Pain improvement was defined in evaluable subjects (subjects with worst pain score [WPS] of 4 at baseline) as a 30% and 2-point decrease in WPS over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management. Pain improvement rate was the number of subjects with pain improvement, divided by the total number of evaluable subjects WPS was the mean of the WPS in the last 24 hours from the preceding 7 days.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2.5 years
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| Notes [23] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Time to pain progression | ||||||||
End point description |
Pain progression was defined in subjects evaluable for pain progression at baseline, i.e., subjects with a WPS of ≤ 7 at the baseline assessment. Pain assessment occurred daily for 1 week, beginning 1 week prior to each visit and including the day of the visit. An evaluable pain assessment interval required completion of a minimum of 4 out of 7 daily questions. Pain progression was defined as the occurrence of either a pain increase or an increase in pain management with respect to baseline, whichever occurred first. An entry of ‘99999’ indicates that the value could not be estimated due to censored values.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2.5 years
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| Notes [24] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to first symptomatic skeletal event (SSE) | ||||||||
End point description |
Time to first symptomatic skeletal event (SSE) is the time (days) from the treatment start date to the first SSE on or following the start date. Subjects not experiencing an SSE at the database cutoff date for primary completion, whether or not surviving, were censored at the last assessment for SSEs. An entry of ‘99999’ indicates that the value could not be estimated due to censored values.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2 years after last treatment
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| Notes [25] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
SSE-free survival | ||||||||
End point description |
The SSE-FS is the time (days) from the treatment start date to the first SSE on or following the start date or death, whichever occurred first. Subjects not experiencing death or an SSE at the database cutoff date for primary completion were censored at the last assessment for SSEs.
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End point type |
Other pre-specified
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End point timeframe |
Up to 2 years after last treatment
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| Notes [26] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with new SSE related AEs during the follow-up period | ||||||||
End point description |
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End point type |
Post-hoc
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End point timeframe |
Up to 2 years after last treatment
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| Notes [27] - Active Follow-up Analysis Set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with new primary malignancies during study treatment or follow-up period | ||||||||
End point description |
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End point type |
Post-hoc
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End point timeframe |
Up to 2 years after last treatment
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| Notes [28] - Active Follow-up Analysis Set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of deaths during study treatment or follow-up period | ||||||||||||||
End point description |
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End point type |
Post-hoc
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End point timeframe |
Up to 2 years after last treatment
|
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| Notes [29] - Safety Analysis Set (SAF) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of subjects with significant meaningful changes for clinical laboratory NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) toxicity grades during the follow-up period | ||||||||
End point description |
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End point type |
Post-hoc
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End point timeframe |
Up to 2 years after last treatment
|
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| Notes [30] - Active Follow-up Analysis Set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with body weight changes during the follow-up period | ||||||||||||||||||||
End point description |
Subjects were counted once during active follow-up for both increases (using the maximum body weight) and decreases (using the minimum body weight).
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End point type |
Post-hoc
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End point timeframe |
Up to 2 years after last treatment
|
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| Notes [31] - Active Follow-up Analysis Set |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of subjects with Eastern Cooperative Oncology Group (ECOG) performance status (PS) score worsened to >=3 during the follow-up period | ||||||||
End point description |
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End point type |
Post-hoc
|
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End point timeframe |
Up to 2 years after last treatment
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| Notes [32] - Active Follow-up Analysis Set |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From start of study treatment until 30 days after last dose of study medication up to 2.5 years
|
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
|
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Reporting groups
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Reporting group title |
Radium-223 dichloride (Xofigo, BAY88-8223)
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Reporting group description |
Subjects received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
19 Nov 2013 |
The following changes were made:
- Terminology changes, including the following which impacted endpoints: the pain endpoint was changed from pain response to pain improvement; skeletal-related event was changed to SSE.
- Clarification of selection criteria of subjects for whom re-treatment was indicated, including baseline rising PSA level and substantial worsening of pain.
- Specified that a separate, extended safety follow-up study protocol is being implemented and will capture the long-term follow-up of subjects on this study.
- The definition of bone progression was revised based on the adapted PCWG2 criteria for consistency across the radium-223 dichloride program.
- Assessment schedules for multiple variables were clarified or updated based on current regulatory requirements and recommendations. |
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Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
