A Phase III Study of Radium-223 Dichloride in Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

Study Overview
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Brief Summary
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ALSYMPCA (ALpharadin in SYMPtomatic Prostate CAncer) is an international Phase III clinical study to evaluate the efficacy and safety of Radium-223 dichloride in patients with hormone refractory prostate cancer and skeletal metastases.

Detailed Description
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The aim of the study was to compare, in patients with symptomatic hormone refractory prostate cancer (HRPC) and skeletal metastases, the efficacy of best standard of care plus Radium-223 dichloride versus best standard of care plus placebo, with the primary efficacy endpoint being overall survival (OS). Patients were randomised in a 2:1 allocation ratio (Radium-223 dichloride:Placebo). The study treatment consisted of 6 intravenous administrations of Radium-223 dichloride or placebo (saline) each separated by an interval of 4 weeks. The patient were followed until 3 years after first study drug administration. Within the U.S., the trial was conducted under an IND sponsored by Bayer HealthCare Pharmaceuticals. All patients received BSoC (Best Standard of Care). This study has the original PCD as 14 October 2010, when a total of 316 deaths had been observed; this resulted in the Independent Data Monitoring Committee's (IDMC's) recommendation to stop the study as the primary efficacy analysis of overall survival had crossed the pre-specified boundary for efficacy. Later an updated analysis of primary endpoint in the first addendum was done with cut-off of 15 July 2011.

Official Title
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A Double-blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

Conditions
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Hormone Refractory Prostate Cancer, Bone Metastases

Intervention / Treatment
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* Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
* Drug: Placebo
* Drug: Best standard of care (BSoC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate Known hormone refractory disease Multiple skeletal metastases (≥ 2 hot spots) on bone scintigraphy No intention to use cytotoxic chemotherapy within the next 6 months Either regular (not occasional) analgesic medication use for cancer related bone pain or treatment with EBRT (External Beam Radiation Therapy) for bone pain Exclusion Criteria: Treatment with an investigational drug within previous 4 weeks, or planned during the treatment period Eligible for first course of docetaxel, i.e. patients who are fit enough, willing and where docetaxel is available Treatment with cytotoxic chemotherapy within previous 4 weeks, or planned during the treatment period, or failure to recover from adverse events due to cytotoxic chemotherapy administered more than 4 weeks ago Systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or rhenium-188 for the treatment of bony metastases within previous 24 weeks Other malignancy treated within the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer) History of visceral metastasis, or visceral metastases as assessed by abdominal/pelvic CT or chest x-ray within previous 8 weeks

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium-223 dichloride (Xofigo, BAY88-8223)<br>Participants received radium-223 50 kilo Becquerel (kBq)/kg body weight (b.w.) for 6 intravenous (IV) administrations separated by 4 weeks intervals plus Best Standard of Care (BSoC). | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br>* Radium-223 dichloride 50 kBq/kg b.w., 6 IV administrations separated by 4 weeks intervals.<br>* Other names: Alpharadin;Drug: Best standard of care (BSoC)<br>* Best standard of care is regarded as the routine standard of care at each center, for example local EBRT (External Beam Radiation Therapy), corticosteroids, antiandrogens, estrogens (e.g., stilboestrol), estramustine or ketoconazole.<br>|
| Placebo Comparator: Placebo<br>Participants received isotonic saline for 6 IV administrations separated by 4 weeks intervals plus Best Standard of Care (BSoC). | Drug: Placebo<br>* Isotonic saline 6 IV administrations separated by 4 weeks intervals.<br>Drug: Best standard of care (BSoC)<br>* Best standard of care is regarded as the routine standard of care at each center, for example local EBRT (External Beam Radiation Therapy), corticosteroids, antiandrogens, estrogens (e.g., stilboestrol), estramustine or ketoconazole.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from date of randomization to the date of death. | From randomization to death due to any cause until approximately 3 years after start of enrollment, the data was collected up to the second data analysis date (15 JUL 2011) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Total Alkaline Phosphatase (ALP) Progression | The time from the first study drug administration to when ALP progression was observed, defined as: 1) In subjects with no ALP decline from baseline; a greater than or equal to 25% increase from baseline value and an increase in absolute value of greater than or equal to 2 ng/mL, at least 12 weeks from baseline; 2) In subjects with initial ALP decline from baseline; the time from start of treatment to first ALP increase that is greater than or equal to 25% increase and at least 2 ng/mL above the nadir value, which was confirmed by a second value obtained 3 or more weeks later | From randomization to first ALP progression until approximately 3 years after start of enrollment | 
| Percentage of Participants With Total ALP Response at Week 12 | ALP levels were measured in participants' blood at Week 12 and compared to baseline values. A confirmed total ALP response (either >/= 30% or 50% reduction from baseline) was confirmed by a second total ALP value approximately 4 weeks later. | At Baseline and Week 12 | 
| Percentage of Participants With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase) | ALP levels were measured in participants' blood at EOT (Week 24) and compared to baseline values. A confirmed total ALP response (>/=50% reduction from baseline) was confirmed by a second total ALP value approximately 4 weeks later. | At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase) | 
| Percentage of Participants With Total ALP Normalization at Week 12 | The return of total ALP value to within normal range at 12 weeks in 2 consecutive measurements (at least 2 weeks apart) after start of treatment in subjects who had ALP above the upper limit of normal (ULN) at baseline. | At Baseline and Week 12 | 
| Percentage Change From Baseline in Total ALP at Week 12 | ALP level was measured in subject's blood at Week 12 and the percent change from the baseline value was calculated (ALP level at week 12 minus ALP level at baseline)/(ALP level at baseline)*100 | At Baseline and Week 12 | 
| Maximum Percentage Decrease From Baseline in Total ALP up to Week 12 | ALP level was measured in participant's blood up to week 12 and the maximum percent decrease from the baseline up to Week 12 value was calculated as the minimum value of [(ALP level up to week 12 minus ALP level at baseline)/(ALP level at baseline)*100] by participant, and set to zero if no decrease from baseline. | From baseline to Week 12 | 
| Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase) | ALP level was measured in subject's blood at EOT (Week 24) and the percent change from the baseline value was calculated (ALP level at EOT minus ALP level at baseline)/(ALP level at baseline)*100 | At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase) | 
| Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment | ALP level was measured in participant's blood during the 24 week treatment (up to EOT) and the maximum percent decrease from baseline during the 24 week treatment value was calculated as the minimum value of [(ALP level up to week 24 minus ALP level at baseline)/(ALP level at baseline)*100] by participant, and set to zero if no decrease from baseline. | From baseline During the 24 Week Treatment | 
| Time to Prostate Specific Antigen (PSA) Progression | The time from the first study drug administration to when PSA progression was observed, defined as: 1) In subjects with no PSA decline from baseline; a greater than or equal to 25% increase from baseline value and an increase in absolute value of greater than or equal to 2 ng/mL, at least 12 weeks from baseline; 2) In subjects with initial PSA decline from baseline; the time from start of treatment to first PSA increase that is greater than or equal to 25% increase and at least 2 ng/mL above the nadir value, which was confirmed by a second value obtained 3 or more weeks later | From randomization to first PSA progression until approximately 3 years after start of enrollment | 
| Percentage of Participants With PSA Response at Week 12 | PSA levels were measured in participants' blood at Week 12 and compared to baseline values. A confirmed PSA response (>/=50% reduction from baseline) was confirmed by a second PSA value approximately 4 weeks later. | At Baseline and Week 12 | 
| Percentage of Participants With PSA Response at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase) | PSA levels were measured in participants' blood at EOT (Week 24) and compared to baseline values. A confirmed PSA response (>/=50% reduction from baseline) was confirmed by a second PSA value approximately 4 weeks later. | At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase) | 
| Percentage Change From Baseline in PSA at Week 12 | PSA level was measured in subject's blood at Week 12 and the percent change from the baseline value was calculated (PSA level at week 12 minus PSA level at baseline)/(PSA level at baseline)*100 | At Baseline and Week 12 | 
| Maximum Percentage Decrease From Baseline in PSA up to Week 12 | PSA level was measured in participant's blood up to Week 12 and the maximum percent decrease from the baseline up to week 12 value was calculated as the minimum value of [(PSA level up to week 12 minus PSA level at baseline)/(PSA level at baseline)*100] by participant, and set to zero if no decrease from baseline. | From baseline up to Week 12 | 
| Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase) | PSA level was measured in subject's blood at EOT (Week 24) and the percent change from the baseline value was calculated (PSA level at EOT minus PSA level at baseline)/(PSA level at baseline)*100 | At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase) | 
| Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period | PSA level was measured in participant's blood during the 24 week treatment (up to EOT) and the maximum percent decrease from baseline during the 24 Week treatment value was calculated as the minimum value of [(PSA level up to week 24 minus PSA level at baseline)/(PSA level at baseline)*100] by participant, and set to zero if no decrease from baseline. | From baseline to End of Treatment (Week 24; 4 weeks post last injection) | 
| Time to First Skeletal Related Event (SRE) | A skeletal related event is the use of external beam radiotherapy to relieve skeletal symptoms or the occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral) or the occurrence of spinal cord compression or a tumour related orthopaedic surgical intervention. For all other events, the start date of the event/medication/therapy was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. | From randomization to first first SRE until approximately 3 years after start of enrollment | 
| Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms | The start date of therapy was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. | From randomization to first EBRT until approximately 3 years after start of enrollment | 
| Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms | The start date of the radioisotopes was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. | From randomization to first use of radioisotopes until approximately 3 years after start of enrollment | 
| Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral | The start date of the event was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. | From randomization to occurrence of first new symptomatic pathological bone fractures until approximately 3 years after start of enrollment | 
| Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention | The start date of the intervention was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. | From randomization to occurrence of first tumor related orthopedic surgical intervention until approximately 3 years after start of enrollment | 
| Time to Occurrence of First Spinal Cord Compression | The start date of the compression was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. | From randomization to first spinal cord compression until approximately 3 years after start of enrollment | 
| Time to Occurrence of First Start of Any Other Anti-cancer Treatment | The start date of the treatment was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date. | From randomization to first start of any other anti-cancer treatment until approximately 3 years after start of enrollment | 
| Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline | ECOG scores were: 0 = fully active; 1 = restricted in physically strenuous activity; 2 = ambulatory and capable of all self-care but unable to work; 3 = capable of only limited self-care; 4 = completely disabled; 5 = death. The visit at which a 2-point or more deterioration in PS was observed was the time of the event. ECOG was assessed at every visit. If a marked deterioration in PS has not occurred at the time of the analysis or the participant was lost to follow-up, the time-to-event variables were censored at the last assessment date. | From randomization to first deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) until approximately 3 years after start of enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormone Refractory Prostate Cancer, Bone Metastases, Radium-223