Prostatic Neoplasms
Conditions
Brief summary
The primary objective in this study is to evaluate bone scan response at Week 24 based on the quantified technetium-99 bone scan lesion area (BSLA). The safety of radium-223 dichloride in combination with abiraterone acetate or enzalutamide will be investigated. The study will evaluate radiological progression free survival, overall survival, and skeletal events. This study will also explore the clinical utility of different imaging modalities (whole body quantified technetium-99 bone scan, DW-MRI \[diffusion-weighted magnetic resonance imaging\] and NaF \[sodium fluoride\] PET-CT \[positron emission tomography-computed tomography\] scan) and will have a separate central radiological review for applicable secondary and exploratory imaging endpoints. All subjects will be randomized as assigned randomly by the IXRS (interactive voice / web response system) system in a 1:1:1 ratio into one of the treatment arms: radium-223 dichloride alone, 50 kBq/kg (55 kBq/kg after implementation of NIST \[National Institute of Standards and Technology\] update) every 4 weeks for up to 6 doses; radium-223 dichloride, 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks up to 6 doses together with abiraterone acetate 1,000 mg daily and prednisone 5 mg bid (twice daily); radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks up to 6 doses together with enzalutamide 160 mg daily. The study will consist of screening, treatment and follow-up periods. Study will continue until disease progression as determined by investigator, or when patient meets criteria for withdrawal from study. Subjects in treatment arms with abiraterone/prednisone or enzalutamide will have the option to continue taking oral study therapy until the end of the study (2 years from the last dose of radium-223 dichloride) if the investigator deems the subject may benefit and there is no clinical or radiological progression. Subjects who discontinue all study treatment prior to 2 years from last radium-223 dichloride treatment will enter active follow-up. During the active follow-up period, the subject will have a safety visit at the clinic every 12 weeks from the EOT (end of treatment) for up to 2 years from the last dose of radium-223 dichloride. Beyond 2 years from last radium-223 dichloride treatment,subjects will enter long-term follow-up and will be followed via phone contact at intervals to assess for safety (hematological toxicity and new primary malignancies) and overall survival. A separate long-term safety follow-up study protocol is planned. Once implemented, the study subjects surviving after the end of the active follow-up will be transitioned to this separate long-term safety follow-up protocol.
Interventions
DRUGRadium-223 dichloride (Xofigo, BAY88-8223)
Radium-223 dichloride (Xofigo, BAY88-8223) 50 kBq/kg (55 kBq/kg after implementation of NIST \[National Institute of Standards and Technology\] update) every 4 weeks x 6 doses intravenous slow bolus
DRUGAbiraterone acetate
Abiraterone acetate 1000 mg (4 x 250 mg tablets) taken orally once daily for up to two years following last dose of radium-223 dichloride
DRUGPrednisone
Prednisone 5 mg capsule taken orally twice daily for up to two years following last dose of radium-223 dichloride
DRUGEnzalutamide
Enzalutamide 160 mg (four 40 mg capsules) taken orally once daily for up to two years following last dose of radium-223 dichloride
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the prostate * Known castration-resistant disease * Serum PSA ≥2 ng/mL (μg/L) * Multiple skeletal metastases (≥2 hot spots) on bone scan * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2. * Life expectancy ≥6 months * Adequate hematologic, hepatic, and renal function
Exclusion criteria
* History of visceral metastasis, or visceral metastases * Malignant lymphadenopathy with lymph nodes exceeding 3 cm in short axis diameter * Medical condition that would make prednisone (corticosteroid) use contraindicated * Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone bid * Treatment with more than one chemotherapy agent for prostate cancer * Prior systemic radiotherapy and hemibody external radiotherapy * History of pituitary or adrenal dysfunction * Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget's disease of bone) * Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy * History of seizures (taking/not taking anticonvulsants), arteriovenous malformation in the brain, head trauma with loss of consciousness * Central nervous system (CNS) metastases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patient Bone Scan Response Rate | At 24 weeks | Radiological bone scan response based on change from baseline of digitized technetium-99 bone scans using computer-aided detection software. Responder (R): 30% or greater resolution of the BSLA compared to baseline. Stable Disease (SD): Not meeting the criteria for R, PD, or UE. Progressive Disease (PD): Two or more new areas of radiotracer uptake attributable to metastatic disease in regions of bone that had not previously shown radiotracer uptake or greater than 30% increase from baseline in BSLA attributable to metastatic disease. Unable to Evaluate (UE): Assigned if bone scan results cannot be interpreted due to inconsistent image acquisition parameters compared to the reference scan, incomplete imaging, or other similar technical deficiencies. |
| Bone Scan Lesion Area | At 24 weeks | Bone scan lesion area was defined as the sum of the pixel areas (cm2) of the set of the whole body technetium-99 bone scan imaging pixels identified as bone lesion. |
Secondary
| Measure | Time frame |
|---|---|
| Time to Radiological Bone Progression | From the randomization date to the date of radiological bone progression (about 30.82 months) |
| Time to First Symptomatic Skeletal Event | From the randomization date to the first SSE on or following the randomization date (about 30.82 months) |
| Radiological Progression Free Survival | From randomization to radiological disease progression or death from any cause (about 30.82 months ) |
| Overall Survival | From the randomization date to the date of death due to any cause (about 42.94 months) |
| Symptomatic Skeletal Event-free Survival | From the randomization date to the first SSE on or following the randomization date or death, whichever occurred first (about 32.39 months) |
| Time to Radiological Progression | From the randomization date to the date of radiological disease progression (about 30.82months) |
Countries
United States
Participant flow
Recruitment details
Study was conducted at 19 study centers in USA from 7-Mar-2014 (first subject's first visit) to 26-Jun-2018 (last subject's last visit).
Pre-assignment details
Overall, 103 subjects were screened. Of them, 68 subjects were randomized, and 63 subjects were received study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Radium-223 Dichloride (Xofigo, BAY88-8223) Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) every 4 weeks x 6 doses IV (slow bolus). | 22 |
| Radium-223 With Abiraterone & Prednision Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus), abiraterone acetate 1000 mg daily, and prednisone 5 mg bid (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection. | 24 |
| Radium-223 With Enzalutamide Participants received radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks x 6 doses (IV slow bolus) and enzalutamide 160 mg daily (oral). The first dose of oral co-medications is to be given after the first radium-223 dichloride injection. | 22 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | AE associated with disease progression | 0 | 1 | 0 |
| Overall Study | AE not assoc. with disease progression | 1 | 4 | 2 |
| Overall Study | Clinical progression | 5 | 7 | 9 |
| Overall Study | Never treated | 3 | 2 | 0 |
| Overall Study | Non-compliance with study drug | 0 | 0 | 1 |
| Overall Study | Radiological progression | 3 | 5 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Radium-223 With Enzalutamide | Radium-223 With Abiraterone & Prednision | Radium-223 Dichloride (Xofigo, BAY88-8223) |
|---|---|---|---|---|
| Age, Continuous | 70.3 Years STANDARD_DEVIATION 9.1 | 71.0 Years STANDARD_DEVIATION 8.7 | 68.6 Years STANDARD_DEVIATION 8.6 | 71.5 Years STANDARD_DEVIATION 10.2 |
| Eastern Cooperative Oncology Group Missing | 5 Participants | 0 Participants | 2 Participants | 3 Participants |
| Eastern Cooperative Oncology Group PS 0 | 34 Participants | 11 Participants | 13 Participants | 10 Participants |
| Eastern Cooperative Oncology Group PS1 | 29 Participants | 11 Participants | 9 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 20 Participants | 23 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 52 Participants | 17 Participants | 17 Participants | 18 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 68 Participants | 22 Participants | 24 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 22 | 1 / 22 |
| other Total, other adverse events | 18 / 19 | 22 / 22 | 22 / 22 |
| serious Total, serious adverse events | 2 / 19 | 10 / 22 | 8 / 22 |
Outcome results
Primary
Bone Scan Lesion Area
Bone scan lesion area was defined as the sum of the pixel areas (cm2) of the set of the whole body technetium-99 bone scan imaging pixels identified as bone lesion.
Time frame: At 24 weeks
Population: Imaging endpt analysis set (IMG): consists of mITT subj. (ITT subj. who received at least one dose of each study drug as randomized) with evaluable imaging scan at baseline, eg. bl quantitated technetium-99 bone scan imaging of sufficient completeness and quality to be assessable and having a non-zero BSLA, as determ. by the central reviewer.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Bone Scan Lesion Area | 30227.13 cm^2 | Standard Deviation 64912.24 |
| Radium-223 With Abiraterone & Prednision | Bone Scan Lesion Area | 10185.58 cm^2 | Standard Deviation 12407.65 |
| Radium-223 With Enzalutamide | Bone Scan Lesion Area | 17321.45 cm^2 | Standard Deviation 22577.59 |
Primary
Patient Bone Scan Response Rate
Radiological bone scan response based on change from baseline of digitized technetium-99 bone scans using computer-aided detection software. Responder (R): 30% or greater resolution of the BSLA compared to baseline. Stable Disease (SD): Not meeting the criteria for R, PD, or UE. Progressive Disease (PD): Two or more new areas of radiotracer uptake attributable to metastatic disease in regions of bone that had not previously shown radiotracer uptake or greater than 30% increase from baseline in BSLA attributable to metastatic disease. Unable to Evaluate (UE): Assigned if bone scan results cannot be interpreted due to inconsistent image acquisition parameters compared to the reference scan, incomplete imaging, or other similar technical deficiencies.
Time frame: At 24 weeks
Population: Imaging endpt analysis set (IMG): consists of mITT subj. (ITT subj. who received at least one dose of each study drug as randomized) with evaluable imaging scan at baseline, eg. bl quantitated technetium-99 bone scan imaging of sufficient completeness and quality to be assessable and having a non-zero BSLA, as determ. by the central reviewer.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Patient Bone Scan Response Rate | Responder (R) | 22.2 Percentage |
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Patient Bone Scan Response Rate | Stable Disease (SD) | 0 Percentage |
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Patient Bone Scan Response Rate | Progressive Disease (PD) | 27.8 Percentage |
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Patient Bone Scan Response Rate | Missing | 50.0 Percentage |
| Radium-223 With Abiraterone & Prednision | Patient Bone Scan Response Rate | Missing | 15.8 Percentage |
| Radium-223 With Abiraterone & Prednision | Patient Bone Scan Response Rate | Responder (R) | 57.9 Percentage |
| Radium-223 With Abiraterone & Prednision | Patient Bone Scan Response Rate | Progressive Disease (PD) | 5.3 Percentage |
| Radium-223 With Abiraterone & Prednision | Patient Bone Scan Response Rate | Stable Disease (SD) | 21.1 Percentage |
| Radium-223 With Enzalutamide | Patient Bone Scan Response Rate | Missing | 18.8 Percentage |
| Radium-223 With Enzalutamide | Patient Bone Scan Response Rate | Stable Disease (SD) | 18.8 Percentage |
| Radium-223 With Enzalutamide | Patient Bone Scan Response Rate | Progressive Disease (PD) | 12.5 Percentage |
| Radium-223 With Enzalutamide | Patient Bone Scan Response Rate | Responder (R) | 50.0 Percentage |
Comparison: H0: Patient bone scan response rate at Week 24 ≤5%. The Type I error rate for the test in each treatment group, is one-sided 0.10. A one-sided p-value will be reported for this test.p-value: 0.0109Clopper and Pearson
Comparison: H0: Patient bone scan response rate at Week 24 ≤5%. The Type I error rate for the test in each treatment group, is one-sided 0.10. A one-sided p-value will be reported for this test.p-value: <0.0001Clopper and Pearson
Comparison: H0: Patient bone scan response rate at Week 24 ≤5%. The Type I error rate for the test in each treatment group, is one-sided 0.10. A one-sided p-value will be reported for this test.p-value: <0.0001Clopper and Pearson
Secondary
Overall Survival
Time frame: From the randomization date to the date of death due to any cause (about 42.94 months)
Population: MITT analysis set: Included all ITT subjects who received at least one dose of each study drug as randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Overall Survival | 35.81 Months |
| Radium-223 With Abiraterone & Prednision | Overall Survival | 37.55 Months |
| Radium-223 With Enzalutamide | Overall Survival | 29.86 Months |
Secondary
Radiological Progression Free Survival
Time frame: From randomization to radiological disease progression or death from any cause (about 30.82 months )
Population: MITT analysis set: Included all ITT subjects who received at least one dose of each study drug as randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Radiological Progression Free Survival | 4.40 Months |
| Radium-223 With Abiraterone & Prednision | Radiological Progression Free Survival | NA Months |
| Radium-223 With Enzalutamide | Radiological Progression Free Survival | NA Months |
Secondary
Symptomatic Skeletal Event-free Survival
Time frame: From the randomization date to the first SSE on or following the randomization date or death, whichever occurred first (about 32.39 months)
Population: MITT analysis set: Included all ITT subjects who received at least one dose of each study drug as randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Symptomatic Skeletal Event-free Survival | 11.93 Months |
| Radium-223 With Abiraterone & Prednision | Symptomatic Skeletal Event-free Survival | NA Months |
| Radium-223 With Enzalutamide | Symptomatic Skeletal Event-free Survival | 19.91 Months |
Secondary
Time to First Symptomatic Skeletal Event
Time frame: From the randomization date to the first SSE on or following the randomization date (about 30.82 months)
Population: MITT analysis set: Included all ITT subjects who received at least one dose of each study drug as randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Time to First Symptomatic Skeletal Event | NA Months |
| Radium-223 With Abiraterone & Prednision | Time to First Symptomatic Skeletal Event | NA Months |
| Radium-223 With Enzalutamide | Time to First Symptomatic Skeletal Event | NA Months |
Secondary
Time to Radiological Bone Progression
Time frame: From the randomization date to the date of radiological bone progression (about 30.82 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Time to Radiological Bone Progression | 11.5 Months |
| Radium-223 With Abiraterone & Prednision | Time to Radiological Bone Progression | NA Months |
| Radium-223 With Enzalutamide | Time to Radiological Bone Progression | NA Months |
Secondary
Time to Radiological Progression
Time frame: From the randomization date to the date of radiological disease progression (about 30.82months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride (Xofigo, BAY88-8223) | Time to Radiological Progression | 4.40 Months |
| Radium-223 With Abiraterone & Prednision | Time to Radiological Progression | NA Months |
| Radium-223 With Enzalutamide | Time to Radiological Progression | NA Months |