Re-treatment Safety of Radium-223 Dichloride in Castration-resistant Prostate Cancer With Bone Metastases

A Re-treatment Safety Study of Radium-223 Dichloride in Subjects With Castration-resistant Prostate Cancer With Bone Metastases Who Received an Initial Course of Six Doses of Radium-223 Dichloride 50 kBq/kg Every Four Weeks

Eligible subjects must have completed 6 doses of treatment of radium-223 dichloride and experienced no radium-223 dichloride-related SAEs (serious adverse events) or CTCAE (Common Terminology Criteria for Adverse Events) Grade 3 or 4 adverse event during or after the initial course of radium-223 dichloride that led to the discontinuation of treatment. 40 Subjects will be enrolled and will receive up to 6 doses of radium-223 dichloride 50 kBq/kg IV every 4 weeks.

The subject will be evaluated for AEs (adverse events) and laboratory tests at each visit every 4 weeks, prior to receiving radium-223 dichloride.

After the end of treatment visit the subjects will enter the active follow up period. Related AEs and SAEs and Lab tests will be evaluated at each visit every 4 weeks for the first 12 weeks, then every 12 weeks for up to 2 years after the last dose of radium-223 dichloride.

After the 2 years of active follow-up, subjects will enter the long-term follow-up period and will be followed via telephone follow-up at 6-month intervals for late toxicities and survival up to 7 years after the last dose of radium-223 dichloride or until death.

Joint safety reviews will regularly take place to oversee safety of the subjects conducted at regular intervals.

An interim analysis of the safety data will be conducted during the study.

Study Overview

• Status: Completed
• Conditions: Prostatic Neoplasms
• Intervention / Treatment: Drug: Radium-223 dichloride (Xofigo, BAY88-8223)

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Finland
  • Kuopio, Finland, 70210
• Israel
  • Haifa, Israel, 3109601
  • Jerusalem, Israel, 9112001
  • Kfar Saba, Israel, 4428164
  • Petah Tikva, Israel, 4941492
• Italy
  • Emilia-Romagna
    • Forlì-Cesena, Emilia-Romagna, Italy, 47014
  • Lombardia
    • Milano, Lombardia, Italy, 20133
• Norway
  • Bergen, Norway, 5021
  • Lørenskog, Norway, 1478
• Spain
  • Barcelona, Spain, 08025
  • Málaga, Spain, 29010
  • Andalucía
    • Córdoba, Andalucía, Spain, 14004
• Sweden
  • Umeå, Sweden, 901 85
• United States
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
  • Nebraska
    • Omaha, Nebraska, United States, 68130
  • New York
    • Syracuse, New York, United States, 13210

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate at any given point in time during disease history
• CRPC (castration-resistant prostate cancer) with clinical or radiologically confirmed bone progression
• Treatment with 6 injections of radium-223 dichloride 50 kBq/kg and no evidence of progression to bone (according to Prostate Cancer Clinical Trials Working Group 2 [PCWG2] criteria) during the first course of treatment
• Signed written informed consent prior to participating in any study related procedures. Willing and able to comply with the protocol, including follow-up visits and examinations

Exclusion Criteria:

• History of a radium-223 dichloride-related serious adverse event (SAE) or CTCAE Grade 3 or 4 adverse event (AE) during or after the initial course of radium-223 dichloride treatment that led to the discontinuation of treatment
• Less than 30 days from the last dose administered in the initial course of radium-223 dichloride treatment
• Visceral metastases 1 cm or greater in largest diameter and / or requiring local or systemic therapeutic intervention, as assessed by abdominal and pelvic magnetic resonance imaging (MRI) / computed tomography (CT) scan and / or chest X-ray within 30 days of the start of treatment
• Lymphadenopathy with lymph nodes exceeding 6 cm in short-axis diameter and / or requiring local or systemic therapeutic intervention. Enlarged lymph nodes of any size if the lymphadenopathy is thought to be a contributor to concurrent hydronephrosis.
• Current central nervous system (CNS) metastases
• Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget's disease of bone)
• Treatment with chemotherapy after the initial course of radium-223 dichloride treatment
• Prior hemibody external radiotherapy
• Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-188

• Any other serious illness or medical conditions

  • Crohn's disease or ulcerative colitis
  • History of documented bone marrow dysplasia
  • Unmanageable fecal incontinence
• Imminent or established spinal cord compression based on clinical findings and / or MRI that has not yet been treated
• Other malignancy treated within the last 3 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radium-223 dichloride (Xofigo, BAY88-8223); Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.	Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Participants received intravenous (IV) injection of radium-223 dichloride 50 kBq/kg body weight every 4 weeks up to 6 injections.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (AEs)	An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. A treatment-emergent adverse events (TEAE) is defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of radium-223 dichloride.	Up to 2.5 years
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)	TESAE occurred after the start of radium-223 dichloride treatment until 30 days after the last dose and results in death; is life-threatening; requires inpatient hospitalization or prolongs existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly / birth defect; is another medically important serious event as judged by the investigator; or is an occurrence of leukemia, myelodysplastic syndrome, aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary malignancy, such as acute myeloid leukemia.	Up to 2.5 years
Number of Participants With Radium-223 Dichloride-related AEs in the Active Follow-up Period	An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study.	Up to 2 years after last treatment
Number of Participants With Radium-223 Dichloride-related SAEs in the Active Follow-up Period	Treatment-related SAE is any SAE that, according to the investigator's causality assessment, is possibly or probably related to treatment with radium-223 dichloride.	Up to 2 years after last treatment
Number of Participants With High/Low Abnormalities in Hematology Variables at Any Visit After Treatment Start		Up to 2.5 years
Number of Participants With High/Low Abnormalities in Biochemistry Variables at Any Visit After Treatment Start		Up to 2.5 years
Number of Participants Who Discontinued Radium-223 Dichloride Treatment Due to Treatment Emergent AEs or Death	An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. A treatment-emergent adverse events (TEAE) is defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of radium-223 dichloride.	Up to 2.5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiological Progression Free Survival (rPFS)	Radiological progression-free survival (rPFS) was defined as the time from the treatment start date to the date of radiological disease progression or death from any cause (if death occurred before such progression), as documented by the investigator. Participants not experiencing death or radiological disease progression at the database cutoff for primary completion were censored at the last radiological disease progression assessment.	Up to 2 years after last treatment
Time to Radiological Bone Progression	Time to radiological bone progression was defined as the time (days) from the treatment start date to the date of radiological bone progression (according to the adapted PCWG2 [Prostate Cancer Clinical Trials Working Group 2] criteria), as documented by the investigator. Participants not experiencing radiological bone progression at the database cutoff for primary completion were censored at the last radiological bone progression assessment.	Up to 2 years after last treatment
Percentage of Participants With Total Alkaline Phosphatase (ALP) Response	Total alkaline phosphatase (ALP) response was defined as ≥ 30% reduction of the blood total ALP level compared with the baseline values. Total ALP response rate was defined as the number of participants with total ALP response divided by the total number of participants evaluable for total ALP response.	Up to 2.5 years
Time to Total ALP Progression	Total ALP progression was defined as a ≥ 25% increase above the nadir (lowest baseline or post-baseline) value to at least 1.5 x ULN (upper limit of normal). The time to total ALP progression was defined as the time (days) from the treatment start date to the date of first total ALP progression. Participants not experiencing ALP progression at the database cutoff date, whether or not surviving, were censored at the last ALP laboratory assessment.	Up to 2 years after last treatment
Percent Change in Total ALP		Baseline and Week 12, Week 24
Percentage of Participants With Prostate Specific Antigen (PSA) Response	Prostate specific antigen (PSA) response was defined as a ≥ 30% reduction of blood PSA level compared with the baseline value, confirmed by a second subsequent PSA value with a ≥ 30% reduction from baseline approximately 4 or more weeks later. Prostate specific antigen response rate was defined as the number of participants with PSA response divided by the total number of participants evaluable for PSA response.	Up to 2.5 years
Time to PSA Progression	Prostate specific antigen progression was defined as a ≥ 25% increase above the nadir (lowest baseline or post-baseline) value, and an increase in absolute value of ≥ 2 ng/mL above nadir. The time to PSA progression was defined as the time (days) from the treatment start date to the date of first PSA progression. Participants without PSA progression as of the database cutoff for primary completion, whether or not surviving, were censored at the last PSA laboratory assessment.	Up to 2 years after last treatment
Overall Survival	Overall survival (OS) was defined as the time (days) from the treatment start date to the date of death due to any cause. For participants who were still alive or who were lost to follow-up as of the database cutoff date for the primary completion, OS was censored at the last known alive date on or prior to the database cutoff date.	Up to 2 years after last treatment
Percentage of Participants With Pain Improvement	Pain improvement was defined in evaluable participants (participants with worst pain score [WPS] of 4 at baseline) as a 30% and 2-point decrease in WPS over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management. Pain improvement rate was the number of participants with pain improvement, divided by the total number of evaluable participants WPS was the mean of the WPS in the last 24 hours from the preceding 7 days.	Up to 2.5 years
Time to Pain Progression	Pain progression was defined in participants evaluable for pain progression at baseline, i.e., participants with a WPS of ≤ 7 at the baseline assessment. Pain assessment occurred daily for 1 week, beginning 1 week prior to each visit and including the day of the visit. An evaluable pain assessment interval required completion of a minimum of 4 out of 7 daily questions. Pain progression was defined as the occurrence of either a pain increase or an increase in pain management with respect to baseline, whichever occurred first.	Up to 2.5 years
Time to First Symptomatic Skeletal Event (SSE)	Time to first symptomatic skeletal event (SSE) is the time (days) from the treatment start date to the first SSE on or following the start date. Participants not experiencing an SSE at the database cutoff date for primary completion, whether or not surviving, were censored at the last assessment for SSEs.	Up to 2 years after last treatment
SSE-free Survival	The SSE-FS is the time (days) from the treatment start date to the first SSE on or following the start date or death, whichever occurred first. Participants not experiencing death or an SSE at the database cutoff date for primary completion were censored at the last assessment for SSEs.	Up to 2 years after last treatment

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Sartor O, Heinrich D, Mariados N, Mendez Vidal MJ, Keizman D, Thellenberg Karlsson C, Peer A, Procopio G, Frank SJ, Pulkkanen K, Rosenbaum E, Severi S, Trigo J, Trandafir L, Wagner V, Li R, Nordquist LT. Re-treatment with radium-223: 2-year follow-up from an international, open-label, phase 1/2 study in patients with castration-resistant prostate cancer and bone metastases. Prostate. 2019 Oct;79(14):1683-1691. doi: 10.1002/pros.23893. Epub 2019 Aug 23.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2013
• Primary Completion (Actual): June 4, 2015
• Study Completion (Actual): April 12, 2017

Study Registration Dates

• First Submitted: August 30, 2013
• First Submitted That Met QC Criteria: August 30, 2013
• First Posted (Estimate): September 4, 2013

Study Record Updates

• Last Update Posted (Actual): March 26, 2018
• Last Update Submitted That Met QC Criteria: March 23, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Antineoplastic Agents; Radium Ra 223 dichloride
• Other Study ID Numbers: 16506; 2013-003046-17 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No