Clinical trial NCT02023697: Standard Dose Versus High Dose and Versus Extended Standard Dose Radium-223 Dichloride in Castration-resistant Prostate Cancer Metastatic to the Bone
Official title: A Three Arm Randomized, Open-label Phase II Study of Radium-223 Dichloride 50 kBq/kg (55 kBq/kg After Implementation of NIST Update) Versus 80 kBq/kg (88 kBq/kg After Implementation of NIST Update), and Versus 50 kBq/kg (55 kBq/kg After Implementation of NIST Update) in an Extended Dosing Schedule in Subjects With Castration-resistant Prostate Cancer Metastatic to the Bone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostatic Neoplasms
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2013-12-30
Enrollment: 391
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: This study will assess different doses and regimens of radium-223 dichloride on the incidence of symptomatic skeletal events. Eligible subjects must have castration resistant prostate cancer with 2 or more skeletal metastases documented within 8 weeks of randomization. Subjects will be randomized to one of 3 treatment arms in a 1:1:1 fashion: a standard regimen of radium-223 dichloride of 50 kBq/kg (55 kBq/kg after implementation of NIST update) injections every month for 6 months, a high dose regimen of 80 kBq/kg (88 kBq/kg after implementation of NIST update)injections every month for 6 months or an extended duration regimen of 50 kBq/kg (55 kBq/kg after implementation of NIST update) injections every month for 12 months. Following the treatment phase, subjects will be followed up every 12 weeks for a minimum of 2 years, at which point they will enter a long term follow-up period during which they are seen every 6 months for up to 7 years after the last dose of radium dichloride. Symptomatic skeletal event and safety endpoints will be assessed at each clinic visit. Pain and analgesic use data will be collected every 4 weeks through Week 48. Additionally, radiological assessments including MRI/CT of the abdomen and pelvis and chest CT, as well as technetium-99 bone scans will be performed at Weeks 8, 16, and 24 and continue every 12 weeks thereafter until disease progression is documented in either the bone or in soft tissue. Radiological imaging will be evaluated by blinded central review.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of the prostate
* Castration-resistant disease defined as:

  * Serum testosterone level: ≤ 50 ng/dL (1.7 nmol/L)
  * Bilateral orchiectomy or maintenance on androgen ablation therapy with luteinizing-hormone-releasing hormone (LHRH) agonist or antagonist, or polyestradiol phosphate
  * Serum PSA (Prostate specific antigen) progression defined as 2 subsequent increases in PSA over a previous reference value (a minimum of 2 ng/mL \[μg/L\]) OR
  * Radiographic evidence of disease progression in bone (according to Prostate Cancer Clinical Trials Working Group 2 \[PCWG2\] criteria) with or without PSA progression
* Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2. In case of ECOG PS 2, the PS has to be due to metastatic prostate cancer to the bone.
* Two or more skeletal metastases (≥ 2 hot spots) on bone scintigraphy within 8 weeks of randomization

Exclusion Criteria:

* History of visceral metastasis, or visceral metastases
* Lymphadenopathy with lymph nodes exceeding 3 cm in short axis diameter
* Central nervous system (CNS) metastases
* Treatment with cytotoxic chemotherapy for prostate cancer within the previous 4 weeks prior to randomization, or planned treatment with cytotoxic chemotherapy agents for prostate cancer during the treatment period or follow-up
* Chronic conditions associated with non-malignant abnormal bone growth (e.g. confirmed Paget's disease of bone)
* Prior treatment with radium-223 dichloride
* Prior systemic radiotherapy and hemibody external radiotherapy

Primary outcomes:
measure: Number of Participants With an Event Defining SSE Free Survival - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Symptomatic Skeletal Event-Free Survival - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With an Event Defining SSE Free Survival - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Symptomatic Skeletal Event-Free Survival - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With an Event Defining SSE Free Survival - Three Dose Groups As Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Symptomatic Skeletal Event Free Survival - Three Dose Groups As Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
Secondary outcomes:
measure: Number of Participants With an Overall Survival Event - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Overall Survival - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With an Overall Survival Event - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Overall Survival - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With an Overall Survival - Three Dose Groups As Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Overall Survival Event - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With First Symptomatic Skeletal Event - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Time to First Symptomatic Skeletal Event - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Time to First Symptomatic Skeletal Event - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With First Symptomatic Skeletal Event - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Time to First Symptomatic Skeletal Event - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With a Radiological Progression Event-Free - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Radiological Progression Free Survival - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With a Radiological Progression Event-Free - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Radiological Progression Free Survival - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With a Radiological Progression Event-Free - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Radiological Progression Free Survival - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With a Radiological Progression Event - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Time to Radiological Progression - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With a Radiological Progression Event - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Time to Radiological Progression - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With a Radiological Progression Event - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Time to Radiological Progression - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Timepoint Pain Improvement Rate - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Timepoint Pain Improvement Rate - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With a Pain Progression Event - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Time to Pain Progression - High Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With a Pain Progression Event - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Time to Pain Progression - Extended Dose vs. Standard Dose
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With a Pain Progression Event - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Time to Pain Progression - Three Dose Groups as Randomized
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
measure: Number of Participants With Treatment-Emergent Adverse Events
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
Other outcomes:
measure: Number of Participants With Change in Analgesic Use From Baseline to Worst Status Post-Baseline
timeFrame: From randomization to 135 SSE-FS events have been observed in comparison 1 or 75 SSE-FS events observed in comparison 2, whichever occurred last (approximately 36 months from first patient randomization)
Locations:
city: Scottsdale
country: United States
state: Arizona
city: New Haven
country: United States
state: Connecticut
city: Fort Myers
country: United States
state: Florida
city: Bethesda
country: United States
state: Maryland
city: Rockville
country: United States
state: Maryland
city: Ann Arbor
country: United States
state: Michigan
city: Detroit
country: United States
state: Michigan
city: Saint Louis
country: United States
state: Missouri
city: Omaha
country: United States
state: Nebraska
city: East Setauket
country: United States
state: New York
city: Portland
country: United States
state: Oregon
city: Pittsburgh
country: United States
state: Pennsylvania
city: Adelaide
country: Australia
state: South Australia
city: Melbourne
country: Australia
state: Victoria
city: Box Hill
country: Australia
city: Darlinghurst
country: Australia
city: Westmead
country: Australia
city: Porto Alegre
country: Brazil
facility: Irmandade Santa Casa de Misericordia de Porto Alegre
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
city: São Paulo
country: Brazil
facility: Instituto do Câncer do Estado de São Paulo
state: Sao Paulo
city: São Paulo
country: Brazil
facility: IBCC - Instituto Brasileiro de Controle do Cancer
state: Sao Paulo
city: São Paulo
country: Brazil
facility: Hospital Israelita Albert Einstein
state: Sao Paulo
city: London
country: Canada
state: Ontario
city: Ottawa
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Santiago
country: Chile
city: Chomutov
country: Czechia
city: Praha 5
country: Czechia
city: Nantes
country: France
city: Vandoeuvre les Nancy
country: France
city: Villejuif Cedex
country: France
city: Tübingen
country: Germany
state: Baden-Württemberg
city: München
country: Germany
state: Bayern
city: Dresden
country: Germany
state: Sachsen
city: Beer Sheva
country: Israel
city: Haifa
country: Israel
city: Jerusalem
country: Israel
city: Kfar Saba
country: Israel
city: Petah Tikva
country: Israel
city: Ramat Gan
country: Israel
city: Meldola
country: Italy
state: Emilia-Romagna
city: Roma
country: Italy
state: Lazio
city: Torino
country: Italy
state: Piemonte
city: Arezzo
country: Italy
state: Toscana
city: Busan
country: Korea, Republic of
state: Busan Gwang''yeogsi
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Hospitalet de Llobregat
country: Spain
state: Barcelona
city: Palma de Mallorca
country: Spain
state: Illes Baleares
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Pamplona
country: Spain
city: Göteborg
country: Sweden
city: Karlstad
country: Sweden
city: Sundsvalls
country: Sweden
city: Umeå
country: Sweden
city: Taipei City
country: Taiwan
state: Taipei
city: Guishan Township
country: Taiwan
state: Taoyuan
city: Kaohsiung
country: Taiwan
city: Taichung
country: Taiwan
city: Taipei
country: Taiwan
city: Bebington
country: United Kingdom
state: Merseyside
city: Taunton
country: United Kingdom
state: Somerset
city: Northwood
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Sternberg CN, Saad F, Graff JN, Peer A, Vaishampayan UN, Leung E, Rosenbaum E, Gurney H, Epstein RJ, Davis ID, Wu B, Trandafir L, Wagner VJ, Hussain M. A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Ann Oncol. 2020 Feb;31(2):257-265. doi: 10.1016/j.annonc.2019.10.025. Epub 2019 Dec 23.