Prostate Cancer
Conditions
Keywords
Prostate Cancer, Bone Metastasis, Symptomatic, Androgen Independent, Hormone Refractory, Castrate Resistant, AIPC, pre-chemotherapy, Post-chemotherapy
Brief summary
This is an open label study designed to examine the effects on concurrent administration of Radium Ra 223 dichloride and Abiraterone Acetate plus Prednisone in subjects with symptomatic castrate resistant prostate cancer and with bone metastases, in both the pre- and post- chemotherapy setting. Both medications are approved by the US Food and Drug Administration for this indication.
Detailed description
Approximately 40 subjects will be enrolled to obtain 30 evaluable subjects. All subjects will receive Radium Ra 223 dichloride every 4 weeks for a total of 6 doses over 24 weeks and concurrent Abiraterone Acetate plus Prednisone for a minimum duration of 26 weeks. Subjects will be evaluated 30 days after the last dose of Radium Ra 223 dichloride. All adverse events deemed to be study related will be followed until resolution. Including screening, the total duration of the study is 32 weeks.
Interventions
DRUGConcurrent use of Radium Ra 223 dichloride and Abiraterone Acetate plus Prednisone
Radium Ra 223 dichloride - A targeted alpha particle-emitting pharmaceutical (a radiopharmaceutical drug) is a ready-to-use solution for intravenous injection containing the drug substance radium dichloride. The active moiety is the alpha particle emitting nuclide Ra-223, present as a divalent cation (223Ra2+) and Abiraterone Acetate - A CYP17 inhibitor, indicated in combination with prednisone for the treatment of subjects with metastatic castration-resistant prostate cancer. Administration of Abiraterone Acetate may result in mineralocorticoid-related adverse events (AEs), due to CYP17 inhibition. Therefore, Abiraterone Acetate is administered in combination with Prednisone to reduce the frequency of these AEs.
Sponsors
Bayer
Carolina Research Professionals, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligible subjects will conform to all of the inclusion criteria listed below: 1. Subject must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure. 2. Subject is willing and able to comply with the protocol, including all study visits and procedures. 3. Subject is a male, greater than 18 years at time of enrollment. 4. Life expectancy of at least 9 months. 5. Subject has histologically documented prostate cancer confirmed by a pathology report from a prostate biopsy or radical prostatectomy specimen. 6. Subject must: • have initiated a stable dose of daily Abiraterone Acetate plus Prednisone within 90 days of enrollment, or • plans to initiate a stable daily dose of Abiraterone plus Prednisone within 30 days of the first Radium Ra 223 dichloride treatment. 7. Subject must plan to receive all 6 Radium Ra 223 dichloride injections and daily oral doses of Abiraterone plus Prednisone during the trial, per protocol. 8. Subject has a history of bone metastasis from prostate cancer as evidenced by imaging performed within 90 days of enrollment from one of the following: • Tc Bone Scan or • Sodium Fluoride PET/CT Scan \*If a bone scan is used, solitary lesions which could be contributed to causes other than prostate cancer must be confirmed with a second modality (i.e.: plain films, CT Scan or MRI. 9. Subject has Castrate Resistant Prostate Cancer, defined as rising PSA with a testosterone level \</= 50ng/dl (2.0 nM/L) while receiving androgen deprivation therapy (medical or surgical castration). \* PSA progression will be defined as at least 2 rising PSA levels taken at least 7 days apart with the 2nd PSA being 2.0 ng/dl or greater. 10. Subject has the presence of bone pain requiring treatment with: 1\) EBRT within the previous 12 weeks prior to enrollment, or 2) Analgesic medications (including but not limited to acetaminophen, NSAIDS, Cox-2 inhibitors, and narcotic Opioids). 11\. Subject has an ECOG performance status of 0-2 at screening 12. Acceptable hematology and serum biochemistry screening values: • White Blood Cell (WBC) \>/= 3,000/mm3 * Absolute Neutrophil Count (ANC) \>1500/mm3 * Platelet (PLT) count \>100,000/mm3 * Hemoglobin (HGB) \> 10.0 g/dL (100g/L; 6.2 mmol/L * Creatinine \<1.5 ULN * Total bilirubin level \<1.5 X ULN * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<2.5 X ULN * albumin \>25 g/L * Baseline electrolytes within normal limits ( Sodium, potassium, chloride, calcium, phosphate, magnesium, LDH, γGT, urea, total protein) 13. Normal Liver Function Tests (LFT) and normal Renal Function Tests (RFT) at screening visit. If the subject has LFT's or RFT's greater than 2.5 times the upper limit of normal (ULN), Medical Monitor review, in conjunction with the subject's PI, will be required. 14\. Subjects receiving Anti-Resorptive medications (such as Zolendronic Acid or denosumab) must be on a stable dose for at least 90 days prior to enrollment (Cycle 1/Week 1/ Day 1). Anti-resorptive medications may be added to the subject's regimen after the End of Treatment visit has been completed. Anti-resorptive medication withdrawal will be allowed per Investigator discretion due to adverse events attributable to that medication. 15\. Subjects of childbearing potential must agree to use adequate contraception beginning at the enrollment until at least 30 days after the last dose of the study drugs. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate.
Exclusion criteria
Eligible subjects must not meet any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria | Subjects were evaluated at the screening visit, monthly during the study, and 30 days after the last dose of Radium Ra 223 dichloride, which will be approximately 32 weeks after the screening visit of evaluable subjects. | Following Quality of Life questionnaires were given at each visit: FACT-P assesses symptoms/problems related to prostate carcinoma and its treatment. It is a combination of the FACT- General + the PCS (Range 1-156, higher scores better). The FACT-General (FACT-G) is a 28 item QOL measure that provides a total score as well as subscale scores: Physical (0-28), Functional (0-28), Social (0-28), Emotional (0-24) Well-being, and Satisfaction with Treatment was not assessed for this study (The total range was between 1-108, higher scores better) FACT-TOI is derived from the sum of the Physical Well-Being, Functional Well-Being, and Prostate Cancer subscale scores; a sensitive measure of patient-reported health (Range 1-104, higher scores better) PCS is a 12-item prostate cancer subscale that asks about symptoms and problems specific to prostate cancer (Range 0-48, higher scores better). |
| Number and Percentage of Participants With Clinically Meaningful Improvement (CMI) in Pain (Between Baseline and End of Treatment) | Subjects were evaluated at the screening visit, monthly during the study, and 30 days after the last dose of Radium Ra 223 dichloride, which will be approximately 32 weeks after the screening visit of evaluable subjects. | Improvement in Bone Pain was assessed using the Bone Pain Inventory (BPI) 1. Pain Severity: Pain severity is the composite of scores of worst pain, least pain, average pain, and pain now. CMI criteria: Decrease \>30% at two consecutive visits in Pain Severity Score in 24 hours without an increase in analgesic use. 2. Pain interference: Pain interference is the composite scores on general activity, mood, walking ability, normal work, relationships with others, sleep and enjoyment of life. CMI criteria: Decrease by 1.25 points or more compared with baseline at two consecutive visits. 3. Transient Pain Flare: Based on the work of Atkinson et al, a transient pain flare was assessed by pain at its worst in 24 hours. CMI criteria: \> 2 points on the BPI-SF Worst Pain scale and subsequent reduction after initiation of Ra-223 and during the first 3 cycles. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Radiologic Assessment Mean Number of Bone Lesions Before and After the Treatment | Baseline and End of Treatment (EOT), approximately 32 weeks from Baseline | \[Not Specified\] |
| Alkaline Phosphatase (ALP) and Prostate Specific Antigen (PSA) Levels Before and After Treatment | Baseline and End of Treatment (EOT), approximately 32 weeks from Baseline | \[Not specified\] |
| Safety Data Was Analyzed and Summarized in Subjects Who Receive at Least One Infusion of Radium Ra 223 Dichloride. Number of Adverse Events Are Being Reported. | Subjects were evaluated at the screening visit, monthly during the study, and 30 days after the last dose of Radium Ra 223 dichloride, which will be approximately 32 weeks after the screening visit of evaluable subjects. | All adverse events relevant to advanced mCRPC subjects as well as adverse events of interest for both Abiraterone Acetate plus Prednisone and Radium Ra 223 dichloride will be reported. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Bone Imaging Response (Number of Participants With Progression and Stable Disease) | Baseline and End of Treatment (EOT), approximately 32 weeks from Baseline | Bone imaging response was assessed at baseline and at EOT visit. Progression was defined as two or more additional lesions in comparison to the baseline. |
| Overall Response Rate | Baseline and End of Treatment (EOT), approximately 32 weeks from Baseline | Determination of measurable disease progression or response was based on modified RECIST criteria. Reported is the number of participants with either a partial or complete response, and who had radiological extraskeletal progression. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone Name of active ingredient Radium Ra 223 dichloride Dose 50 kBq/kg body weight Route of Administration Intravenous Duration of Treatment One injection every 4 weeks X 6 injections maximum.
Name of active ingredient Abiraterone Acetate plus Prednisone Dose 1000 mg/day and 5 mg BID Route of Administration Oral Duration of Treatment 26 weeks minimum duration. There is no maximum duration. | 36 |
| Total | 36 |
Baseline characteristics
| Characteristic | Radium 223 With Concomitant Abiraterone Acetate and Prednisone |
|---|---|
| Age, Continuous | 75 years |
| Race/Ethnicity, Customized African American | 8 Participants |
| Race/Ethnicity, Customized Caucasian | 28 Participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 36 Participants |
| Region of Enrollment United States | 36 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 36 |
| other Total, other adverse events | 30 / 36 |
| serious Total, serious adverse events | 5 / 36 |
Outcome results
Primary
Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria
Following Quality of Life questionnaires were given at each visit: FACT-P assesses symptoms/problems related to prostate carcinoma and its treatment. It is a combination of the FACT- General + the PCS (Range 1-156, higher scores better). The FACT-General (FACT-G) is a 28 item QOL measure that provides a total score as well as subscale scores: Physical (0-28), Functional (0-28), Social (0-28), Emotional (0-24) Well-being, and Satisfaction with Treatment was not assessed for this study (The total range was between 1-108, higher scores better) FACT-TOI is derived from the sum of the Physical Well-Being, Functional Well-Being, and Prostate Cancer subscale scores; a sensitive measure of patient-reported health (Range 1-104, higher scores better) PCS is a 12-item prostate cancer subscale that asks about symptoms and problems specific to prostate cancer (Range 0-48, higher scores better).
Time frame: Subjects were evaluated at the screening visit, monthly during the study, and 30 days after the last dose of Radium Ra 223 dichloride, which will be approximately 32 weeks after the screening visit of evaluable subjects.
Population: Improvement at the EOT visit was defined as increase from baseline of \>= 10 points for FACT-P Total Scale. \>9 points for FACT-G Total and FACT-TOI scales, and \>=3 points for the remaining scales.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria | FACT-P Total Scale | 20 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria | FACT-G Total Scale | 18 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria | Treatment Outcome Index (FACT-TOI) | 18 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria | Prostate Cancer Subscale (PCS) | 25 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria | Physical Well-being | 19 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria | Functional Well-being | 17 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria | Emotional Well-being | 18 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (Between Baseline and End of Treatment) in Quality-of-Life Determined by the Minimum Increase From Baseline in Scores as Per the QOL CMI Criteria | Social Well-being | 15 Participants |
Primary
Number and Percentage of Participants With Clinically Meaningful Improvement (CMI) in Pain (Between Baseline and End of Treatment)
Improvement in Bone Pain was assessed using the Bone Pain Inventory (BPI) 1. Pain Severity: Pain severity is the composite of scores of worst pain, least pain, average pain, and pain now. CMI criteria: Decrease \>30% at two consecutive visits in Pain Severity Score in 24 hours without an increase in analgesic use. 2. Pain interference: Pain interference is the composite scores on general activity, mood, walking ability, normal work, relationships with others, sleep and enjoyment of life. CMI criteria: Decrease by 1.25 points or more compared with baseline at two consecutive visits. 3. Transient Pain Flare: Based on the work of Atkinson et al, a transient pain flare was assessed by pain at its worst in 24 hours. CMI criteria: \> 2 points on the BPI-SF Worst Pain scale and subsequent reduction after initiation of Ra-223 and during the first 3 cycles.
Time frame: Subjects were evaluated at the screening visit, monthly during the study, and 30 days after the last dose of Radium Ra 223 dichloride, which will be approximately 32 weeks after the screening visit of evaluable subjects.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (CMI) in Pain (Between Baseline and End of Treatment) | Pain Severity | 18 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (CMI) in Pain (Between Baseline and End of Treatment) | Pain Interference | 12 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Number and Percentage of Participants With Clinically Meaningful Improvement (CMI) in Pain (Between Baseline and End of Treatment) | Transient Pain Flare | 2 Participants |
Secondary
Alkaline Phosphatase (ALP) and Prostate Specific Antigen (PSA) Levels Before and After Treatment
\[Not specified\]
Time frame: Baseline and End of Treatment (EOT), approximately 32 weeks from Baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Alkaline Phosphatase (ALP) and Prostate Specific Antigen (PSA) Levels Before and After Treatment | ALP (Baseline) | 261 ng/dL | Standard Deviation 284 |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Alkaline Phosphatase (ALP) and Prostate Specific Antigen (PSA) Levels Before and After Treatment | ALP (EOT) | 110 ng/dL | Standard Deviation 187 |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Alkaline Phosphatase (ALP) and Prostate Specific Antigen (PSA) Levels Before and After Treatment | PSA (Baseline) | 87 ng/dL | Standard Deviation 233 |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Alkaline Phosphatase (ALP) and Prostate Specific Antigen (PSA) Levels Before and After Treatment | PSA (EOT) | 137 ng/dL | Standard Deviation 441 |
p-value: <0.00001t-test, 2 sided
p-value: 0.487t-test, 2 sided
Secondary
Radiologic Assessment Mean Number of Bone Lesions Before and After the Treatment
\[Not Specified\]
Time frame: Baseline and End of Treatment (EOT), approximately 32 weeks from Baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Radiologic Assessment Mean Number of Bone Lesions Before and After the Treatment | Baseline | 11.6 Lesions | Standard Deviation 2.8 |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Radiologic Assessment Mean Number of Bone Lesions Before and After the Treatment | EOT | 5.6 Lesions | Standard Deviation 2.4 |
Secondary
Safety Data Was Analyzed and Summarized in Subjects Who Receive at Least One Infusion of Radium Ra 223 Dichloride. Number of Adverse Events Are Being Reported.
All adverse events relevant to advanced mCRPC subjects as well as adverse events of interest for both Abiraterone Acetate plus Prednisone and Radium Ra 223 dichloride will be reported.
Time frame: Subjects were evaluated at the screening visit, monthly during the study, and 30 days after the last dose of Radium Ra 223 dichloride, which will be approximately 32 weeks after the screening visit of evaluable subjects.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Safety Data Was Analyzed and Summarized in Subjects Who Receive at Least One Infusion of Radium Ra 223 Dichloride. Number of Adverse Events Are Being Reported. | Overall Adverse Events | 186 Adverse Events |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Safety Data Was Analyzed and Summarized in Subjects Who Receive at Least One Infusion of Radium Ra 223 Dichloride. Number of Adverse Events Are Being Reported. | Grade I or II Adverse Events | 179 Adverse Events |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Safety Data Was Analyzed and Summarized in Subjects Who Receive at Least One Infusion of Radium Ra 223 Dichloride. Number of Adverse Events Are Being Reported. | Treatment Related Adverse Events | 70 Adverse Events |
Other Pre-specified
Bone Imaging Response (Number of Participants With Progression and Stable Disease)
Bone imaging response was assessed at baseline and at EOT visit. Progression was defined as two or more additional lesions in comparison to the baseline.
Time frame: Baseline and End of Treatment (EOT), approximately 32 weeks from Baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Bone Imaging Response (Number of Participants With Progression and Stable Disease) | Stable Disease | 29 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Bone Imaging Response (Number of Participants With Progression and Stable Disease) | Progression | 2 Participants |
Other Pre-specified
Overall Response Rate
Determination of measurable disease progression or response was based on modified RECIST criteria. Reported is the number of participants with either a partial or complete response, and who had radiological extraskeletal progression.
Time frame: Baseline and End of Treatment (EOT), approximately 32 weeks from Baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Overall Response Rate | Partial or complete response | 4 Participants |
| Radium 223 With Concomitant Abiraterone Acetate and Prednisone | Overall Response Rate | Progression | 8 Participants |