Prostate Cancer
Conditions
Brief summary
This is a Phase II non-blinded randomized study evaluating men with oligometastatic prostate cancer lesions randomized (1:1) to stereotactic ablative radiation therapy (SABR) versus SBAR + Radium-223. We are looking to determine the progression-free survival of men who have oligometastatic prostate cancer with at least one bone metastasis with stereotactic ablative radiation therapy (SABR) versus SABR + Radium-223.
Detailed description
The metastatic capacity of prostate cancer (PCa) behaves along a spectrum of disease that contains an oligometastatic state where metastases are limited in number and location. The importance of local consolidation of all tumor deposits in oligometastatic disease to forestall further metastatic dissemination is now backed by small randomized studies. Our previous Baltimore ORIOLE randomized trial of stereotactic ablative radiation (SABR) alone, highly focused, high-dose radiation, versus observation in oligometastatic PCa final data demonstrate a progression-free survival (PFS) benefit of SABR alone. The patterns of failure from our ORIOLE trial in combination with prior data suggest one dominant mode of failure is from microscopic disease particularly those with bone-tropic biology. These are important early clinical data suggesting the existence of an oligometastatic state and the importance of local therapies in the management of these patients. Radiopharmaceutical therapy (RPT) approaches have not been applied in the oligometastatic space and thus the opportunity to target micrometastatic disease in conjunction with local consolidation of macroscopic disease with SABR has the potential to provide a curative paradigm for patients with oligometastatic PCa. We introduce the successor trial to ORIOLE called RAVENS that is a phase II randomized trial of SABR +/- the bone metastasis seeking RPT Xofigo in men with oligometastatic PCa. We hypothesize macroscopic prostate tumors support the growth of and help nurture future distant metastases and this process can be impacted most by total, macro- and microscopic, tumor consolidation. In addition, we hypothesize that circulating biomarkers can identify men with oligometastasis that benefit the most from SABR and RPT.
Interventions
DRUGRadium-223
Radium-223 plus SABR will be within two weeks.
SABR 1-5 fractions
Sponsors
Congressionally Directed Medical Research Programs
Bayer
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
RAdium-223 and SABR Versus SABR (Stereotactic Ablative Radiotherapy)
Eligibility
Sex/Gender
MALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Patient must have at least one and up to three asymptomatic metastatic tumor(s) of the bone or soft tissue (with at least one bone metastasis) develop within the past 6-months that are ≤ 5.0 cm or \<250 cm3 * Patient must have had their primary tumor treated with surgery and/or radiation. * Histologic confirmation of malignancy (primary or metastatic tumor). * PSADT \<15 months. PSA doubling time (PSADT) will be calculated using as many PSA values that are available from time of relapse (PSA \> 0.2). To calculate PSADT, the Memorial Sloan Kettering Cancer Center Prostate Cancer Prediction Tool will be used. It can be found at the following web site: https://www.mskcc.org/nomograms/prostate/psa-doubling-time. * Patient may have had prior systemic therapy and/or ADT associated with treatment of their primary prostate cancer. Patient may have had ADT associated with salvage radiation therapy (to the primary prostate cancer or pelvis is allowed). * PSA \> 0.5 but \<50. * Testosterone \> 125 ng/dL. * Patient must be ≥ 18 years of age. * Patient must have a life expectancy ≥ 12 months. * Patient must have an ECOG performance status ≤ 2. * Patient must have normal organ and marrow function as defined as: Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. \* Patient must have the ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* No more than 3 years of ADT is allowed, with the most recent ADT treatment having occurred greater than 6 months prior to enrollment. * PSMA-PET/MRI or PSMA-PET/CT scan within the past 6 months with results that demonstrate more disease lesions than baseline CT/Bone Scan * Castration-resistant prostate cancer (CRPC). * Spinal cord compression or impending spinal cord compression. * Suspected pulmonary and/or liver metastases (greater \>10 mm in largest axis). * Patient receiving any other investigational agents. * Patient receiving abiraterone and prednisone. * Patient is participating in a concurrent treatment protocol. * Serum creatinine \> 3 times the upper limit of normal. * Total bilirubin \> 3 times the upper limit of normal. * Liver Transaminases \> 5-times the upper limit of normal. * Unable to lie flat during or tolerate PET/MRI, PET/CT or SBRT. * Prior salvage treatment to the primary prostate cancer or pelvis is allowed. * Refusal to sign informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Up to 24 months | Time to progression in men who have oligometastatic prostate cancer after therapy. Progression is defined by PCWG2 criteria as follows: \>=25% increase in PSA from nadir (and by \>=2ng/mL), and/or clinical/radiographic progression (clinical progression = symptomatic progression, worsening of disease-related symptoms or new cancer-related complications; radiographic progression on CT scan defined by RECIST 1.1 criteria: \>=20% enlargement in sum diameter of soft-tissue target lesions; or on bone scan \>=1 new bone lesions), initiation of ADT or death due to any cause, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Local Control at 12 Months | Up to 12 months | Percentage of participants achieving local control at 12 months |
| Time to Locoregional Progression | 12 months | Time from starting treatment until local and/or regional relapse is documented |
| Time to Distant Progression | Up to 24 months | Time from starting treatment until distant relapse is documented |
| Metastasis-Free Survival | Up to 24 months | Time from treatment start to the time of a newly documented tumor metastasis by CT and/or bone scan. Subjects who do not progress will be censored at the time of the last contact. |
| Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Up to 24 months | Adverse events grade 3 or higher (defined by CTCAE v4.0) measured as treatment related events in either SABR or SABR and Radium-223 arms. |
| Quality of Life as Assessed by Pain Severity and Pain Interference Score With Imputations Using the Brief Pain Inventory | Baseline, Day 360 | The brief pain inventory assesses the severity of pain, location of pain, amount of pain over the last 24 hours, and impact of pain on daily functions. Scores for the 4 pain severity items and 7 pain interference items range from 0-10, where 10 is the worst pain or pain that completely interferes with described activity and 0 is the least pain or does not interfere with described activity. The mean of these scores is used to measure pain severity and pain interference. |
| Change in Quality of Life as Assessed by Pain Severity and Pain Interference With Imputations Using the Brief Pain Inventory | Baseline, Day 360 | The brief pain inventory assesses the severity of pain, location of pain, amount of pain over the last 24 hours, and impact of pain on daily functions. Scores for the 4 pain severity items and 7 pain interference items range from 0-10, where 10 is the worst pain or pain that completely interferes with described activity and 0 is the least pain or does not interfere with described activity. The mean of these scores is used to measure pain severity and pain interference. |
| Time to New Metastatsis | 12 months | Time to New Metastasis (TNM) is defined as the time from starting treatment to the time of a new documented tumor metastasis by CT and/or bone scan. Subjects who do not progress will be censored at the time of the last contact. |
| Duration of Response | 12 Months | Response will be defined as evidence of CR, PR, or stable disease. The duration of response will be measured from the start of treatment until the criteria for progression are met |
| Androgen-deprivation Therapy (ADT)-Free Survival | Up to 24 months | Time from randomization until initiation of androgen-deprivation therapy (ADT). ADT Free Survival (ADT-FS) is defined as the time from starting treatment to the time of initiation of palliative ADT. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Radium-223 and SABR First radium-223 infusion will be within two weeks of SABR
Radium-223: Radium-223 plus SABR will be within two weeks.
stereotactic ablative radiotherapy (SABR): SABR 1-5 fractions | 30 |
| SABR SABR(1-5 fractions) will be administered for all men
stereotactic ablative radiotherapy (SABR): SABR 1-5 fractions | 33 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Patient withdrew before intervention | 1 | 0 |
Baseline characteristics
| Characteristic | Radium-223 and SABR | SABR | Total |
|---|---|---|---|
| Age, Continuous | 66 years | 69 years | 68 years |
| Baseline PSA, ng/mL | 6.20 ng/mL STANDARD_DEVIATION 8.24 | 5.08 ng/mL STANDARD_DEVIATION 5.88 | 5.61 ng/mL STANDARD_DEVIATION 7.06 |
| Bone Lesions Number 1 | 20 Participants | 24 Participants | 44 Participants |
| Bone Lesions Number 2 | 6 Participants | 9 Participants | 15 Participants |
| Bone Lesions Number 3 | 4 Participants | 0 Participants | 4 Participants |
| Bone Lesions Type Lesions outside pelvis/vertebra | 11 Participants | 15 Participants | 26 Participants |
| Bone Lesions Type No lesion outside pelvis/vertebra | 19 Participants | 18 Participants | 37 Participants |
| Extra-pelvic lymph nodes No | 28 Participants | 31 Participants | 59 Participants |
| Extra-pelvic lymph nodes Yes | 2 Participants | 2 Participants | 4 Participants |
| Initial Imaging Type Conventional and non-PSMA-PET | 8 Participants | 9 Participants | 17 Participants |
| Initial Imaging Type Conventional and PSMA-PET | 9 Participants | 8 Participants | 17 Participants |
| Initial Imaging Type Conventional Only | 6 Participants | 3 Participants | 9 Participants |
| Initial Imaging Type Non-PSMA-PET Only | 2 Participants | 4 Participants | 6 Participants |
| Initial Imaging Type PSMA -PET Only | 5 Participants | 9 Participants | 14 Participants |
| Initial Lesion Bone and Lymph node | 9 Participants | 5 Participants | 14 Participants |
| Initial Lesion Bone Only | 21 Participants | 28 Participants | 49 Participants |
| Initial Management/Treatment Radiation | 5 Participants | 7 Participants | 12 Participants |
| Initial Management/Treatment Surgery | 25 Participants | 26 Participants | 51 Participants |
| International Society of Urological Pathology (ISUP) Group Grade ISUP Group Grade 1-3 | 17 Participants | 12 Participants | 29 Participants |
| International Society of Urological Pathology (ISUP) Group Grade ISUP Group Grade 4-5 | 13 Participants | 21 Participants | 34 Participants |
| Previous Hormone Therapy No | 9 Participants | 11 Participants | 20 Participants |
| Previous Hormone Therapy Yes | 21 Participants | 22 Participants | 43 Participants |
| Race/Ethnicity, Customized African American | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 27 Participants | 29 Participants | 56 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 28 Participants | 31 Participants | 59 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Canada | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment United States | 25 Participants | 28 Participants | 53 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 30 Participants | 33 Participants | 63 Participants |
| Total Lesion Number 1 Lesion | 14 Participants | 20 Participants | 34 Participants |
| Total Lesion Number 2 Lesions | 7 Participants | 10 Participants | 17 Participants |
| Total Lesion Number 3 Lesions | 8 Participants | 2 Participants | 10 Participants |
| Total Lesion Number 4 Lesions | 0 Participants | 1 Participants | 1 Participants |
| Total Lesion Number 5 Lesions | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 33 |
| other Total, other adverse events | 30 / 31 | 33 / 33 |
| serious Total, serious adverse events | 0 / 31 | 0 / 33 |
Outcome results
Primary
Progression-free Survival
Time to progression in men who have oligometastatic prostate cancer after therapy. Progression is defined by PCWG2 criteria as follows: \>=25% increase in PSA from nadir (and by \>=2ng/mL), and/or clinical/radiographic progression (clinical progression = symptomatic progression, worsening of disease-related symptoms or new cancer-related complications; radiographic progression on CT scan defined by RECIST 1.1 criteria: \>=20% enlargement in sum diameter of soft-tissue target lesions; or on bone scan \>=1 new bone lesions), initiation of ADT or death due to any cause, whichever occurs first.
Time frame: Up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 and SABR | Progression-free Survival | 10.5 Months |
| SABR | Progression-free Survival | 11.8 Months |
Secondary
Androgen-deprivation Therapy (ADT)-Free Survival
Time from randomization until initiation of androgen-deprivation therapy (ADT). ADT Free Survival (ADT-FS) is defined as the time from starting treatment to the time of initiation of palliative ADT.
Time frame: Up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 and SABR | Androgen-deprivation Therapy (ADT)-Free Survival | 16.2 Months |
| SABR | Androgen-deprivation Therapy (ADT)-Free Survival | 19.2 Months |
Secondary
Change in Quality of Life as Assessed by Pain Severity and Pain Interference With Imputations Using the Brief Pain Inventory
The brief pain inventory assesses the severity of pain, location of pain, amount of pain over the last 24 hours, and impact of pain on daily functions. Scores for the 4 pain severity items and 7 pain interference items range from 0-10, where 10 is the worst pain or pain that completely interferes with described activity and 0 is the least pain or does not interfere with described activity. The mean of these scores is used to measure pain severity and pain interference.
Time frame: Baseline, Day 360
Population: Participants with missing data, and further 2 participants were not assessed due to disease progression for SBRT group and SBRT+Ra223 group, respectively.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Radium-223 and SABR | Change in Quality of Life as Assessed by Pain Severity and Pain Interference With Imputations Using the Brief Pain Inventory | 0.34 score on a scale |
| SABR | Change in Quality of Life as Assessed by Pain Severity and Pain Interference With Imputations Using the Brief Pain Inventory | -0.01 score on a scale |
Secondary
Duration of Response
Response will be defined as evidence of CR, PR, or stable disease. The duration of response will be measured from the start of treatment until the criteria for progression are met
Time frame: 12 Months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 and SABR | Duration of Response | 10.5 Months |
| SABR | Duration of Response | 11.8 Months |
Secondary
Metastasis-Free Survival
Time from treatment start to the time of a newly documented tumor metastasis by CT and/or bone scan. Subjects who do not progress will be censored at the time of the last contact.
Time frame: Up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 and SABR | Metastasis-Free Survival | 12.3 Months |
| SABR | Metastasis-Free Survival | 19.4 Months |
Secondary
Quality of Life as Assessed by Pain Severity and Pain Interference Score With Imputations Using the Brief Pain Inventory
The brief pain inventory assesses the severity of pain, location of pain, amount of pain over the last 24 hours, and impact of pain on daily functions. Scores for the 4 pain severity items and 7 pain interference items range from 0-10, where 10 is the worst pain or pain that completely interferes with described activity and 0 is the least pain or does not interfere with described activity. The mean of these scores is used to measure pain severity and pain interference.
Time frame: Baseline, Day 360
Population: Participants with missing data, and further 2 participants were not assessed due to disease progression for SBRT group and SBRT+Ra223 group, respectively.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Radium-223 and SABR | Quality of Life as Assessed by Pain Severity and Pain Interference Score With Imputations Using the Brief Pain Inventory | Baseline BPI Score | 0.31 score on a scale |
| Radium-223 and SABR | Quality of Life as Assessed by Pain Severity and Pain Interference Score With Imputations Using the Brief Pain Inventory | Day 360 BPI Score | 0.56 score on a scale |
| SABR | Quality of Life as Assessed by Pain Severity and Pain Interference Score With Imputations Using the Brief Pain Inventory | Baseline BPI Score | 0.39 score on a scale |
| SABR | Quality of Life as Assessed by Pain Severity and Pain Interference Score With Imputations Using the Brief Pain Inventory | Day 360 BPI Score | 0.27 score on a scale |
Secondary
Rate of Local Control at 12 Months
Percentage of participants achieving local control at 12 months
Time frame: Up to 12 months
Population: One patient in the SABR arm never received imaging (data not collected) afterward due to loss of follow up/died for other reasons, so that patient will be censored out or excluded.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Radium-223 and SABR | Rate of Local Control at 12 Months | 0.794 percentage of participants |
| SABR | Rate of Local Control at 12 Months | 0.908 percentage of participants |
Secondary
Time to Distant Progression
Time from starting treatment until distant relapse is documented
Time frame: Up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 and SABR | Time to Distant Progression | 11.9 Months |
| SABR | Time to Distant Progression | 12.1 Months |
Secondary
Time to Locoregional Progression
Time from starting treatment until local and/or regional relapse is documented
Time frame: 12 months
Population: There were no locoregional progression events at the site of SBRT during the time patients were on study.
Secondary
Time to New Metastatsis
Time to New Metastasis (TNM) is defined as the time from starting treatment to the time of a new documented tumor metastasis by CT and/or bone scan. Subjects who do not progress will be censored at the time of the last contact.
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 and SABR | Time to New Metastatsis | 11.9 Months |
| SABR | Time to New Metastatsis | 12.0 Months |
Secondary
Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0)
Adverse events grade 3 or higher (defined by CTCAE v4.0) measured as treatment related events in either SABR or SABR and Radium-223 arms.
Time frame: Up to 24 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium-223 and SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Grade 3 or higher Adverse Events | 5 Participants |
| Radium-223 and SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Insomnia | 0 Participants |
| Radium-223 and SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Lymphocyte Count Decrease | 4 Participants |
| Radium-223 and SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Musculoskeletal Pain | 1 Participants |
| Radium-223 and SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Fatigue | 0 Participants |
| SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Musculoskeletal Pain | 0 Participants |
| SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Grade 3 or higher Adverse Events | 3 Participants |
| SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Fatigue | 1 Participants |
| SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Lymphocyte Count Decrease | 1 Participants |
| SABR | Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) | Insomnia | 1 Participants |