Clinical trial NCT00699751: A Phase III Study of Radium-223 Dichloride in Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hormone Refractory Prostate Cancer
Bone Metastases
Keywords: Hormone Refractory Prostate Cancer
Bone Metastases
Radium-223
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2008-06-18
Enrollment: 921
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival
timeFrame: 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 outcomes:
measure: Time to Total Alkaline Phosphatase (ALP) Progression
timeFrame: From randomization to first ALP progression until approximately 3 years after start of enrollment
measure: Percentage of Participants With Total ALP Response at Week 12
timeFrame: At Baseline and Week 12
measure: 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)
timeFrame: At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)
measure: Percentage of Participants With Total ALP Normalization at Week 12
timeFrame: At Baseline and Week 12
measure: Percentage Change From Baseline in Total ALP at Week 12
timeFrame: At Baseline and Week 12
measure: Maximum Percentage Decrease From Baseline in Total ALP up to Week 12
timeFrame: From baseline to Week 12
measure: Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)
timeFrame: At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)
measure: Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment
timeFrame: From baseline During the 24 Week Treatment
measure: Time to Prostate Specific Antigen (PSA) Progression
timeFrame: From randomization to first PSA progression until approximately 3 years after start of enrollment
measure: Percentage of Participants With PSA Response at Week 12
timeFrame: At Baseline and Week 12
measure: Percentage of Participants With PSA Response at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)
timeFrame: At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)
measure: Percentage Change From Baseline in PSA at Week 12
timeFrame: At Baseline and Week 12
measure: Maximum Percentage Decrease From Baseline in PSA up to Week 12
timeFrame: From baseline up to Week 12
measure: Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)
timeFrame: At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)
measure: Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period
timeFrame: From baseline to End of Treatment (Week 24; 4 weeks post last injection)
measure: Time to First Skeletal Related Event (SRE)
timeFrame: From randomization to first first SRE until approximately 3 years after start of enrollment
measure: Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms
timeFrame: From randomization to first EBRT until approximately 3 years after start of enrollment
measure: Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms
timeFrame: From randomization to first use of radioisotopes until approximately 3 years after start of enrollment
measure: Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral
timeFrame: From randomization to occurrence of first new symptomatic pathological bone fractures until approximately 3 years after start of enrollment
measure: Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention
timeFrame: From randomization to occurrence of first tumor related orthopedic surgical intervention until approximately 3 years after start of enrollment
measure: Time to Occurrence of First Spinal Cord Compression
timeFrame: From randomization to first spinal cord compression until approximately 3 years after start of enrollment
measure: Time to Occurrence of First Start of Any Other Anti-cancer Treatment
timeFrame: From randomization to first start of any other anti-cancer treatment until approximately 3 years after start of enrollment
measure: Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline
timeFrame: From randomization to first deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) until approximately 3 years after start of enrollment
Other outcomes:
measure: Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0.
timeFrame: Week 0
measure: Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8.
timeFrame: Week 8
measure: Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16.
timeFrame: Week 16
measure: Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24.
timeFrame: Week 24
measure: Absolute Scores for Functional Assessment of Cancer Therapy - Prostate (FACT-P) Trial Outcome Index (TOI)
timeFrame: Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)
measure: Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
timeFrame: Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)
measure: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 16
timeFrame: At Week 16
measure: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 24
timeFrame: At Week 24
measure: Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Follow-up Visit 2 (Week 42)
timeFrame: At Follow-up Visit 2 (Week 42)
measure: Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
timeFrame: At Week 16, Week 24, and Follow-up Visit 2 (Week 42)
measure: Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
timeFrame: Baseline, Week 16, Week 24, and Follow-up Visit 2 (week 42)
measure: Absolute Scores for Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
timeFrame: At Week 16, Week 24, and Follow-up Visit 2 (Week 42)
measure: Change From Baseline for FACT-G Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)
timeFrame: Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)
measure: Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 16
timeFrame: Week 16
measure: Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 24
timeFrame: Week 24
measure: Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Follow-up Visit 8 (Week 139)
timeFrame: Follow-up Visit 8 (Week 139)
Locations:
city: Los Angeles
country: United States
state: California
city: Roseville
country: United States
state: California
city: Tampa
country: United States
state: Florida
city: New Orleans
country: United States
state: Louisiana
city: St. Louis
country: United States
state: Missouri
city: Las Vegas
country: United States
state: Nevada
city: Philadelphia
country: United States
state: Pennsylvania
city: Liverpool
country: Australia
state: New South Wales
city: Randwick
country: Australia
state: New South Wales
city: St Leonards
country: Australia
state: New South Wales
city: Sydney
country: Australia
state: New South Wales
city: Wahroonga
country: Australia
state: New South Wales
city: Wollongong
country: Australia
state: New South Wales
city: Brisbane
country: Australia
state: Queensland
city: Toowoomba
country: Australia
state: Queensland
city: Adelaide
country: Australia
state: South Australia
city: Adelaide
country: Australia
state: South Australia
city: Hobart
country: Australia
state: Tasmania
city: Fitzroy
country: Australia
state: Victoria
city: Nedlands
country: Australia
state: Western Australia
city: Kortrijk
country: Belgium
city: Ottignies
country: Belgium
city: Salvador
country: Brazil
state: Bahia
city: Belo Horizonte
country: Brazil
state: Minas Gerais
city: Porto Alegre
country: Brazil
state: Rio Grande do Sul
city: Barretos
country: Brazil
state: Sao Paulo
city: Piracicaba
country: Brazil
state: Sao Paulo
city: Belo Horizonte
country: Brazil
city: Rio de Janeiro
country: Brazil
city: Sao Paulo
country: Brazil
city: Edmonton
country: Canada
state: Alberta
city: London
country: Canada
state: Ontario
city: Ottawa
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Brno
country: Czech Republic
city: Chomutov
country: Czech Republic
city: Olomouc
country: Czech Republic
city: Ostrava
country: Czech Republic
city: Plzen - Bory
country: Czech Republic
city: Praha 4
country: Czech Republic
city: Usti nad Labem
country: Czech Republic
city: La Roche Sur Yon
country: France
city: Montbeliard
country: France
city: Saint Cloud
country: France
city: Ulm
country: Germany
state: Baden-Württemberg
city: Frankfurt
country: Germany
state: Hessen
city: Marburg
country: Germany
state: Hessen
city: Göttingen
country: Germany
state: Niedersachsen
city: Hannover
country: Germany
state: Niedersachsen
city: Dortmund
country: Germany
state: Nordrhein-Westfalen
city: Mainz
country: Germany
state: Rheinland-Pfalz
city: Berlin
country: Germany
city: Berlin
country: Germany
city: Hamburg
country: Germany
city: Chai Wan
country: Hong Kong
city: Hong Kong
country: Hong Kong
city: Hongkong
country: Hong Kong
city: Kowloon
country: Hong Kong
city: Beer Sheva
country: Israel
city: Kfar Saba
country: Israel
city: Tel Aviv
country: Israel
city: Zrifin
country: Israel
city: Meldola
country: Italy
state: Forlì
city: Candiolo
country: Italy
state: Torino
city: Bergamo
country: Italy
city: Milano
country: Italy
city: Reggio Emilia
country: Italy
city: Alkmaar
country: Netherlands
city: Nijmegen
country: Netherlands
city: Rotterdam
country: Netherlands
city: Bergen
country: Norway
city: Bodø
country: Norway
city: Kristiansand
country: Norway
city: Oslo
country: Norway
city: Oslo
country: Norway
city: Tromsø
country: Norway
city: Trondheim
country: Norway
city: Ålesund
country: Norway
city: Bydgoszcz
country: Poland
city: Gliwice
country: Poland
city: Kielce
country: Poland
city: Krakow
country: Poland
city: Luiblin
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Wroclaw
country: Poland
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Banska Bystrica
country: Slovakia
city: Bratislava
country: Slovakia
city: Bratislava
country: Slovakia
city: Martin
country: Slovakia
city: Presov
country: Slovakia
city: Trnava
country: Slovakia
city: Santiago de Compostela
country: Spain
state: A Coruña
city: Alcorcón
country: Spain
state: Madrid
city: Barakaldo
country: Spain
state: Vizcaya
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Córdoba
country: Spain
city: Pamplona
country: Spain
city: Valencia
country: Spain
city: Zaragoza
country: Spain
city: Göteborg
country: Sweden
city: Jönköping
country: Sweden
city: Kalmar
country: Sweden
city: Malmö
country: Sweden
city: Sandviken
country: Sweden
city: Stockholm
country: Sweden
city: Sundsvall
country: Sweden
city: Umeå
country: Sweden
city: Romford
country: United Kingdom
state: Essex
city: Leicester
country: United Kingdom
state: Leicestershire
city: Bebington
country: United Kingdom
state: Merseyside
city: Nottingham
country: United Kingdom
state: Nottinghamshire
city: Taunton
country: United Kingdom
state: Somerset
city: Ipswich
country: United Kingdom
state: Suffolk
city: Guildford
country: United Kingdom
state: Surrey
city: Sutton
country: United Kingdom
state: Surrey
city: Coventry
country: United Kingdom
state: Warwickshire
city: Birmingham
country: United Kingdom
state: West Midlands
city: Belfast
country: United Kingdom
city: Brighton
country: United Kingdom
city: Bristol
country: United Kingdom
city: Cardiff
country: United Kingdom
city: Derby
country: United Kingdom
city: Hull
country: United Kingdom
city: Leeds
country: United Kingdom
city: Manchester
country: United Kingdom
city: Northwood
country: United Kingdom
city: Plymouth
country: United Kingdom
city: Sheffield
country: United Kingdom
city: Southampton
country: United Kingdom
city: Wolverhampton
country: United Kingdom
Study officials:
affiliation: The Royal Marsden Hospital, UK
name: Christopher Parker, MD
role: STUDY_CHAIR
References:
citation: Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzen L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland OS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. doi: 10.1056/NEJMoa1213755.
citation: Hoskin P, Sartor O, O'Sullivan JM, Johannessen DC, Helle SI, Logue J, Bottomley D, Nilsson S, Vogelzang NJ, Fang F, Wahba M, Aksnes AK, Parker C. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014 Nov;15(12):1397-406. doi: 10.1016/S1470-2045(14)70474-7. Epub 2014 Oct 17.
citation: Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Bruland OS, Parker C. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014 Jun;15(7):738-46. doi: 10.1016/S1470-2045(14)70183-4. Epub 2014 May 13.
citation: Delacruz A, Arauz G, Curley T, Lindo A, Jensen T. Nursing management of patients with castration-resistant prostate cancer undergoing radium-223 dichloride treatment. Clin J Oncol Nurs. 2015 Apr;19(2):E31-5. doi: 10.1188/15.CJON.E31-E35.
citation: Humm JL, Sartor O, Parker C, Bruland OS, Macklis R. Radium-223 in the treatment of osteoblastic metastases: a critical clinical review. Int J Radiat Oncol Biol Phys. 2015 Apr 1;91(5):898-906. doi: 10.1016/j.ijrobp.2014.12.061.
citation: Nilsson S. Alpha-emitter radium-223 in the management of solid tumors: current status and future directions. Am Soc Clin Oncol Educ Book. 2014:e132-9. doi: 10.14694/EdBook_AM.2014.34.e132.
citation: Den RB, Doyle LA, Knudsen KE. Practical guide to the use of radium 223 dichloride. Can J Urol. 2014 Apr;21(2 Supp 1):70-6.
citation: Shirley M, McCormack PL. Radium-223 dichloride: a review of its use in patients with castration-resistant prostate cancer with symptomatic bone metastases. Drugs. 2014 Apr;74(5):579-86. doi: 10.1007/s40265-014-0198-4.
citation: Wissing MD, van Leeuwen FW, van der Pluijm G, Gelderblom H. Radium-223 chloride: Extending life in prostate cancer patients by treating bone metastases. Clin Cancer Res. 2013 Nov 1;19(21):5822-7. doi: 10.1158/1078-0432.CCR-13-1896. Epub 2013 Sep 19.
citation: Joung JY, Ha YS, Kim IY. Radium Ra 223 dichloride in castration-resistant prostate cancer. Drugs Today (Barc). 2013 Aug;49(8):483-90. doi: 10.1358/dot.2013.49.8.1968670.
citation: Parker C, Zhan L, Cislo P, Reuning-Scherer J, Vogelzang NJ, Nilsson S, Sartor O, O'Sullivan JM, Coleman RE. Effect of radium-223 dichloride (Ra-223) on hospitalisation: An analysis from the phase 3 randomised Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. Eur J Cancer. 2017 Jan;71:1-6. doi: 10.1016/j.ejca.2016.10.020. Epub 2016 Dec 6.