Study NCT04237584
A Study Comparing ARB With Radium-223 vs ARB Therapy With Placebo and the Effect Upon Survival for mCRPC Patients (ESCALATE)
Submitted Date:  July 22, 2022 (v9)
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General Comments

Quality Control Review Comment provided by the National Library of Medicine:

  1. This record has new issues that must be addressed.
Open or close this module Study Identification
Unique Protocol ID: PC18-1005
Brief Title: A Study Comparing ARB With Radium-223 vs ARB Therapy With Placebo and the Effect Upon Survival for mCRPC Patients (ESCALATE)
Official Title: ESCALATE, A Phase III Randomized Study Comparing Enzalutamide or Darolutamide With Radium-223 vs Enzalutamide or Darolutamide With Placebo and the Effect Upon Symptomatic Skeletal Event-Free Survival for mCRPC Patients
Secondary IDs:
Open or close this module Study Status
Record Verification: July 2022
Overall Status: Terminated [The study was stopped due to insurmountable enrollment challenges affecting trial accrual, resulting from the rapidly evolving treatment options for advanced prostate cancer.]
Study Start: June 30, 2020
Primary Completion: March 7, 2022 [Actual]
Study Completion: March 7, 2022 [Actual]
First Submitted: January 15, 2020
First Submitted that
Met QC Criteria:
January 21, 2020
First Posted: January 23, 2020 [Actual]
Last Update Submitted that
Met QC Criteria:
Last Update Posted: August 16, 2022 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: MANA RBM
Responsible Party: Sponsor
Collaborators: Bayer
Carolina Urologic Research Center
Tulane University
Barbara Ann Karmanos Cancer Institute
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: No
Open or close this module Study Description
Brief Summary: This is a randomized, multi-center, double-blind, Phase III study of radium-223 plus enzalutamide or darolutamide compared to enzalutamide or darolutamide treatment plus placebo.
Detailed Description: The hypothesis investigators will test in this study is whether layering radium-223 following 16 weeks of enzalutamide or darolutamide exposure in patients demonstrating a biochemical response improves disease outcomes. By adding radium-223 following a potential bone flare phenomenon [after first 12-14 weeks of therapy with an androgen receptor blocker (ARB)], including patients expected to have durable response to systemic therapy, and mandating the use of bone protective agents during treatment, the investigators aim to demonstrate an optimal time to add radium-223 in the mCRPC landscape.
Open or close this module Conditions
Conditions: Metastatic Castration-resistant Prostate Cancer
Keywords: mCRPC
ARB
Radiopharmaceutical
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Sequential Assignment
12 week lead-in open-label androgen-receptor blocker (ARB) followed by up to 6 cycles of double-blind Radium-223 or placebo.
Number of Arms: 6
Masking: Double (Participant, Investigator)
Allocation: Randomized
Enrollment: 23 [Actual]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Enzalutamide during Lead-in Period
Randomized, open-label lead-in ARB (enzalutamide tablets, 160 mg PO QD) for 12 weeks.
Drug: Enzalutamide during Lead-in Period
Participants will receive 12 weeks open-label lead-in ARB (enzalutamide) that will continue after double-blind randomization to radium-223 or placebo.
Other Names:
  • Xtandi
Active Comparator: Lead-in Enzalutamide followed by Radium-223/Enzalutamide
Randomized, open-label lead-in ARB (enzalutamide) for 12 weeks followed by randomized, double-blind Radium-223 IV at 55 kBq/kg IV up to 6 cycles (at 4 week intervals) with continued randomized open-label enzalutamide.
Drug: Lead-in Enzalutamide followed by Radium-223/Enzalutamide
After a 12-week lead-in period of open-label enzalutamide, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label enzalutamide.
Other Names:
  • Xofigo, Xtandi
Placebo Comparator: Lead-in Enzalutamide followed by Placebo/Enzalutamide
Randomized, open-label lead-in ARB (enzalutamide) for 12 weeks followed by randomized, double-blind normal saline placebo IV up to 6 cycles (at 4 week intervals) with continued randomized open-label enzalutamide.
Drug: Lead-in Enzalutamide followed by Placebo/Enzalutamide
After a 12-week lead-in period of open-label enzalutamide, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label enzalutamide.
Other Names:
  • Placebo, Xtandi
Darolutamide during Lead-in Period
Randomized, open-label lead-in ARB (darolutamide tablets, 300 mg PO BID) for 12 weeks.
Drug: Darolutamide during Lead-in Period
Participants will receive 12 weeks open-label lead-in darolutamide that will continue after double-blind randomization to radium-223 or placebo.
Other Names:
  • Nubeqa
Active Comparator: Lead-in Darolutamide followed by Radium-223/Darolutamide
Randomized, open-label lead-in ARB (darolutamide) for 12 weeks followed by randomized, double-blind Radium-223 IV at 55 kBq/kg IV up to 6 cycles (at 4 week intervals) with continued randomized open-label darolutamide.
Drug: Lead-in Darolutamide followed by Radium-223/Darolutamide
After a 12-week lead-in period of open-label darolutamide, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label darolutamide.
Other Names:
  • Xofigo, Nubeqa
Placebo Comparator: Lead-in Darolutamide followed by Placebo/Darolutamide
Randomized, open-label lead-in ARB (darolutamide) for 12 weeks followed by randomized, double-blind normal saline placebo IV up to 6 cycles (at 4 week intervals) with continued randomized open-label darolutamide.
Drug: Lead-in Darolutamide followed by Placebo/Darolutamide
After a 12-week lead-in period of open-label darolutamide, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label darolutamide.
Other Names:
  • Placebo, Nubeqa
Open or close this module Outcome Measures
[See Results Section.]
Primary Outcome Measures:
1. Symptomatic Skeletal Event-free Survival (SSE-FS)
[ Time Frame: approximately 1 year and 8 months ]

SSE-FS is a composite endpoint, composed of 4 events that indicate disease progression:

  • the first use of external-beam radiation therapy to relieve skeletal tumor-related symptoms
  • the occurrence of new symptomatic pathologic bone fractures.
  • the occurrence of new symptomatic spinal cord compression
  • a tumor-related orthopedic surgical intervention
Secondary Outcome Measures:
1. Overall Survival (OS)
[ Time Frame: approximately 1 year and 8 months ]

Number of subjects who survived between RT2 randomization through data cut-off.
2. Time to Chemotherapy Initiation
[ Time Frame: approximately 1 year and 8 months ]

Number of subjects who began docetaxel or cabazitaxel treatment during the study.
3. Radiographic Progression-free Survival (rPFS)
[ Time Frame: approximately 1 year and 8 months ]

Number of subjects with bone scan progression per PCWG3 criteria, and/or progression by CT/MRI per RECIST 1.1 criteria, or death from any cause following RT2. Radiological progression is interpreted by local assessment only.
4. Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223.
[ Time Frame: approximately 1 year and 8 months ]

Safety profile of androgen receptor blockers (enzalutamide or darolutamide) with or without radium-223; number of participants with treatment-related adverse events as assessed by CTCAE v5.0. Reported only in the AE reporting module.
5. Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic)
[ Time Frame: approximately 1 year and 8 months ]

Assess occurrence of AESI: fractures (pathologic and non-pathologic).
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: Male
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  1. Able and willing to provide informed consent.
  2. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma.
  3. Men ≥ 18 years.
  4. ECOG performance status of 0 or 1 at screening.
  5. Metastatic to bone with ≥ 2 bone metastases (area of increased uptake on 99mTc bone scan); equivocal lesions on the bone scan must be confirmed by standard X-ray, CT, or MRI.
  6. Patients must have progressive metastatic castration-resistant prostate cancer (mCRPC) at screening and on androgen deprivation therapy (ADT) as evidenced by either:
    1. For patients who manifest disease progression solely as a rising prostate-specific antigen (PSA) level - documentation of a sequence of two rising PSA values at a minimum of 1-week apart with the Screening value ≥1 ng/ml (see Appendix D);
    2. For patients with disease progression manifested in the bone, irrespective of progression by rising PSA - defined by the appearance of 2 or more new skeletal lesions demonstrated by 99Tc bone imaging. Ambiguous results should be confirmed by other imaging modalities than bone scan and x-ray (e.g.: CT-scan or MRI).
    3. For patients with disease progression manifested at nodal sites, irrespective of progression by rising PSA - progression defined per RECIST 1.1.
  7. Ongoing ADT with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy.
  8. Use of bone health agents (denosumab or zoledronic acid or other bisphosphonates) starting any time prior to R1 unless contraindicated or considered not in the best interest of the patient. A waiver must be approved by the medical monitor if bone health agents cannot be used. Bone health agents should be continued throughout both RT1 and RT2 treatment periods.
  9. Adequate bone marrow and organ function as defined by:
    1. Hemoglobin ≥ 10.0 g/dL
    2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    3. Platelets ≥ 100 x 109/L
    4. Serum creatinine ≤ 1.95 mg/dL
    5. Estimated creatinine clearance >/= 30 mL/min by Cockroft-Gault calculation
    6. Alanine aminotransferase (ALT) ≤ 175 U/L
    7. Aspartate aminotransferase (AST) ≤ 100 U/L
    8. Total bilirubin ≤ 1.8 mg/dL (unless the patient a diagnosis of Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin; in patients with Gilbert's, the total bilirubin should be less than 6 mg/dL if patient has Gilbert's and the elevation should be seen in the unconjugated or indirect bilirubin measurement)
    9. LDH ≤ 224 U/L at screening.
    10. Albumin ≥ 2.5 g/dL
  10. Fertile male patients, defined as all males physiologically capable of conceiving offspring with female partners of child-bearing potential, must be willing to use condoms plus spermicidal agent during the study treatment period and for 6 months after the last dose of study drug, and not father a child or donate sperm during this period.
  11. The treating site investigator deems RT1 (Enzalutamide or Darolutamide) treatment safe and feasible.

    Subjects must meet the remaining inclusion criteria in order to be qualified for the second randomization (R2). Only subjects that complete the initial 12 weeks of run-in RT1 should be evaluated. Prior inclusion criteria do not need to be re-evaluated:

  12. Patients must have a documented ≥ 30% decline of PSA at any time during the 12 weeks of RT1.
  13. Patients must have no evidence of visceral metastatic disease at the time of RT2 randomization
  14. Ongoing treatment with RT1 and bone health agents at time of RT2 randomization.
  15. The treating site investigator deems RT2 (Ra-223 dichloride) treatment safe and feasible.

Exclusion Criteria:

  1. Pathological finding consistent with small cell carcinoma of the prostate.
  2. Prior chemotherapy for CRPC. Prior docetaxel for hormone-sensitive disease is permitted under the following conditions: started within 3 months of ADT initiation, given for a maximum of 6 cycles and progression occurred > 6 months after the last dose of docetaxel.
  3. Prior treatment for mCRPC or CRPC. However, the following therapies are permitted and not exclusionary: Sipuleucel-T, 5-alpha-reductase inhibitors, estrogens, or older antiandrogens (such as flutamide, bicalutamide, or nilutamide).
  4. Prior treatment for more than 2 months with CYP17 inhibitors (e.g. abiraterone or orteronel).
  5. Prior treatment for more than 2 months with agents inhibiting androgen receptor signaling (e.g. enzalutamide, apalutamide, or darolutamide).
  6. Prior hemibody or whole-body external radiotherapy. Other types of prior external radiotherapy and brachytherapies are allowed.
  7. Prior therapy with radionuclides (e.g., radium-223, strontium-89, samarium-153, rhenium-186, rhenium-188, actinium-225 and lutetium-177).
  8. Current involvement in any drug or device trial involving investigational agent or medical device within the last 28 days prior to R1.
  9. In general, any prior investigational agent for nmCRPC/mCRPC; however, may be reviewed by medical monitor/PIs for waiver consideration, on a case-by-case basis.
  10. Hypersensitivity to compounds related to enzalutamide, darolutamide, or Ra-223.
  11. A blood transfusion ≤ 28 days prior to R1.
  12. Major surgical procedures ≤ 28 days or minor surgical procedures ≤7 days prior to R1. No waiting period is required following port-a-cath placement.
  13. Patients with visceral metastases, clinical evidence of central nervous system metastases, or leptomeningeal tumor spread as demonstrated via CT/MRI of chest, abdomen, pelvis, and CNS (if needed). CT/MRI of the CNS only performed if suspicion of CNS metastases or leptomeningeal tumor spread. Nodules < 1 cm alone will not be considered visceral metastases. Renal masses < 3 cm will not be considered exclusionary.
  14. Serious active infection at the time of screening or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.
  15. Presence of other active cancers, or history of treatment for invasive cancer ≤2 years of R1. Patients with Stage I/II cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) and superficial bladder cancer are eligible, as are patients with history of non-melanoma skin cancer.
  16. Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results.
Open or close this module Contacts/Locations
Study Officials: Neal Shore, MD
Study Chair
Carolina Urologic Research Center
Locations: United States, South Carolina
Research Site
Myrtle Beach, South Carolina, United States, 29572
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations:
Links:
Available IPD/Information:
Open or close this module Document Section
Study Protocol and Statistical Analysis Plan
Document Date: May 4, 2020
Uploaded: 06/16/2022 12:43
File Name: Prot_SAP_002.pdf
Informed Consent Form
Document Date: April 1, 2020
Uploaded: 05/23/2022 15:39
File Name: ICF_001.pdf
Study Results
Open or close this module Participant Flow
Recruitment Details Recruitment occurred from Jun 2020- Jul 2021 at selected medical centers that specialized in the treatment of advanced prostate cancer.
Pre-assignment Details 23 subjects signed ICF. 2/23 subjects screen failed without reporting any adverse events and received no study treatments. 21/23 subjects signing ICF met all entry criteria and were randomized to Lead-in ARB (R1). 5 subjects discontinued the study during Lead-in ARB. Although 16 subjects randomized to R2, 2 of the subjects randomized to Enzalutamide + Placebo did not receive any cycles due to the early termination of the study and are reported only in the Lead-in Enzalutamide safety group.
 
Arm/Group Title Enzalutamide + Ra-223 Darolutamide + Ra-223 Enzalutamide + Placebo Darolutamide + Placebo
Arm/Group Description Lead-in Enzalutamide 12 weeks followed by Ra-223 up to 6 cycles (at 4 week intervals) with continued Enzalutamide. Lead-in Darolutamide 12 weeks followed by Ra-223 up to 6 cycles (at 4 week intervals) with continued Darolutamide. Lead-in Enzalutamide 12 weeks followed by Placebo (normal saline) up to 6 cycles (at 4 week intervals) with continued Enzalutamide. Lead-in Darolutamide 12 weeks followed by Placebo (normal saline) up to 6 cycles (at 4 week intervals) with continued Darolutamide.
Period Title: R1- Lead-in ARB Treatment (12 Weeks)
Started 5 5 6 5
Completed 4 4 3 3
Not Completed 1 1 3 2
Reason Not Completed
Adverse Event 0 0 1 1
Did not meet R2 entry criteria 1 1 0 1
Randomized R2 (no cycles given) 0 0 2 0
Period Title: R2- ARB Treatment With Ra-223 or Placebo
Started 4 4 3 3
Completed 0 0 0 0
Not Completed 4 4 3 3
Reason Not Completed
Sponsor Decision 4 4 2 3
Physician Decision 0 0 1 0
Open or close this module Baseline Characteristics
Arm/Group TitleLead-in Enzalutamide Followed by Radium-223/EnzalutamideLead-in Darolutamide Followed by Radium-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/DarolutamideTotal
Arm/Group Description12-week lead-in of open-label Enzalutamide followed by radium-223. Participants continued on their randomized, open-label Enzalutamide.12-week lead-in of open-label Darolutamide followed by radium-223. Participants continued on their randomized, open-label Darolutamide.12-week lead-in of open-label Enzalutamide followed by placebo. Participants continued on their randomized, open-label Enzalutamide.12-week lead-in of open-label Darolutamide followed by placebo. Participants continued on their randomized, open-label Darolutamide.Total of all reporting groups
Overall Number of Baseline Participants 5 5 6 5 21
Baseline Analysis Population Description [Not Specified]
Age, Categorical
Measure Type: Count of Participants
Unit of measure: Participants
Number Analyzed5 Participants5 Participants6 Participants5 Participants21 Participants
<=18 years
0
0%
0
0%
0
0%
0
0%
0
0%
Between 18 and 65 years
0
0%
0
0%
0
0%
1
20%
1
4.76%
>=65 years
5
100%
5
100%
6
100%
4
80%
20
95.24%
Sex/Gender, Customized
Measure Type: Number
Unit of measure: participants
Number Analyzed5 Participants5 Participants6 Participants5 Participants21 Participants
Males
556521
Ethnicity (NIH/OMB)
Measure Type: Count of Participants
Unit of measure: Participants
Number Analyzed5 Participants5 Participants6 Participants5 Participants21 Participants
Hispanic or Latino
0
0%
1
20%
0
0%
1
20%
2
9.52%
Not Hispanic or Latino
5
100%
4
80%
6
100%
4
80%
19
90.48%
Unknown or Not Reported
0
0%
0
0%
0
0%
0
0%
0
0%
Race (NIH/OMB)
Measure Type: Count of Participants
Unit of measure: Participants
Number Analyzed5 Participants5 Participants6 Participants5 Participants21 Participants
American Indian or Alaska Native
0
0%
0
0%
0
0%
0
0%
0
0%
Asian
0
0%
0
0%
0
0%
0
0%
0
0%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
0
0%
0
0%
Black or African American
0
0%
1
20%
1
16.67%
0
0%
2
9.52%
White
5
100%
4
80%
5
83.33%
5
100%
19
90.48%
More than one race
0
0%
0
0%
0
0%
0
0%
0
0%
Unknown or Not Reported
0
0%
0
0%
0
0%
0
0%
0
0%
Region of Enrollment
Measure Type: Number
Unit of measure: participants
Number Analyzed5 Participants5 Participants6 Participants5 Participants21 Participants
United States
556521
Concomitant use of bone health agents (osteoclast inhibitors)
Measure Type: Count of Participants
Unit of measure: Participants
Number Analyzed5 Participants5 Participants6 Participants5 Participants21 Participants
556521
Open or close this module Outcome Measures
1. Primary Outcome:
Title Symptomatic Skeletal Event-free Survival (SSE-FS)
Description

SSE-FS is a composite endpoint, composed of 4 events that indicate disease progression:

  • the first use of external-beam radiation therapy to relieve skeletal tumor-related symptoms
  • the occurrence of new symptomatic pathologic bone fractures.
  • the occurrence of new symptomatic spinal cord compression
  • a tumor-related orthopedic surgical intervention
Time Frame approximately 1 year and 8 months
Outcome Measure Data
Analysis Population Description
No analysis was performed. Outcome measure includes only number (%) of subjects that met primary endpoint (occurrence of SSE-FS).
 
Arm/Group TitleLead-in Enzalutamide Only (no Cycles)Lead-in Darolutamide Only (no Cycles)Lead-in Enzalutamide Followed by Radium-223/EnzalutamideLead-in Darolutamide Followed by Radium-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/Darolutamide
Arm/Group DescriptionLead-in Enzalutamide only. No Cycles.Lead-in Darolutamide only. No Cycles.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Radium-223 + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Radium-223 + Darolutamide.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Placebo + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Placebo + Darolutamide.
Overall Number of Participants Analyzed4 3 4 4 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
0
0%
0
0%
0
0%
0
0%
2
66.7%
1
33.3%
2. Secondary Outcome:
Title Overall Survival (OS)
Description Number of subjects who survived between RT2 randomization through data cut-off.
Time Frame approximately 1 year and 8 months
Outcome Measure Data
Analysis Population Description
No analysis was performed. Outcome measure includes only number (%) of subjects with who survived.
 
Arm/Group TitleLead-in Enzalutamide Only (no Cycles)Lead-in Darolutamide Only (no Cycles)Lead-in Enzalutamide Followed by Radium-223/EnzalutamideLead-in Darolutamide Followed by Radium-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/Darolutamide
Arm/Group DescriptionLead-in Enzalutamide only. No Cycles.Lead-in Darolutamide only. No Cycles.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Radium-223 + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Radium-223 + Darolutamide.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Placebo + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Placebo + Darolutamide.
Overall Number of Participants Analyzed4 3 4 4 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
4
100%
3
100%
4
100%
4
100%
3
100%
3
100%

Quality Control Review Comment provided by the National Library of Medicine:

  1. Information here appears inconsistent with information in other parts of the record.
3. Secondary Outcome:
Title Time to Chemotherapy Initiation
Description Number of subjects who began docetaxel or cabazitaxel treatment during the study.
Time Frame approximately 1 year and 8 months
Outcome Measure Data
Analysis Population Description
No analysis was performed. Outcome measure includes only number (%) of subjects who started docetaxel or cabazitaxel treatment during the study.
 
Arm/Group TitleLead-in Enzalutamide Only (no Cycles)Lead-in Darolutamide Only (no Cycles)Lead-in Enzalutamide Followed by Radium-223/EnzalutamideLead-in Darolutamide Followed by Radium-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/Darolutamide
Arm/Group DescriptionLead-in Enzalutamide only. No Cycles.Lead-in Darolutamide only. No Cycles.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Radium-223 + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Radium-223 + Darolutamide.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Placebo + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Placebo + Darolutamide.
Overall Number of Participants Analyzed4 3 4 4 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
4. Secondary Outcome:
Title Radiographic Progression-free Survival (rPFS)
Description Number of subjects with bone scan progression per PCWG3 criteria, and/or progression by CT/MRI per RECIST 1.1 criteria, or death from any cause following RT2. Radiological progression is interpreted by local assessment only.
Time Frame approximately 1 year and 8 months
Outcome Measure Data
Analysis Population Description
No analysis was performed. Outcome measure includes only number (%) of subjects who experienced radiological progression.
 
Arm/Group TitleLead-in Enzalutamide Only (no Cycles)Lead-in Darolutamide Only (no Cycles)Lead-in Enzalutamide Followed by Radium-223/EnzalutamideLead-in Darolutamide Followed by Radium-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/Darolutamide
Arm/Group DescriptionLead-in Enzalutamide only. No Cycles.Lead-in Darolutamide only. No Cycles.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Radium-223 + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Radium-223 + Darolutamide.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Placebo + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Placebo + Darolutamide.
Overall Number of Participants Analyzed4 3 4 4 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
0
0%
0
0%
0
0%
0
0%
1
33.3%
1
33.3%
5. Secondary Outcome:
Title Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223.
Description Safety profile of androgen receptor blockers (enzalutamide or darolutamide) with or without radium-223; number of participants with treatment-related adverse events as assessed by CTCAE v5.0. Reported only in the AE reporting module.
Time Frame approximately 1 year and 8 months
Outcome Measure Data
Analysis Population Description
No analysis was performed. Outcome measure includes only number (%) of subjects followed for safety. Safety data reported in AE section.
 
Arm/Group TitleLead-in Enzalutamide Only (no Cycles)Lead-in Darolutamide Only (no Cycles)Lead-in Enzalutamide Followed by Radium-223/EnzalutamideLead-in Darolutamide Followed by Radium-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/Darolutamide
Arm/Group DescriptionLead-in Enzalutamide only. No Cycles.Lead-in Darolutamide only. No Cycles.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Radium-223 + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Radium-223 + Darolutamide.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Placebo + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Placebo + Darolutamide.
Overall Number of Participants Analyzed4 3 4 4 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
4
100%
3
100%
4
100%
4
100%
3
100%
3
100%
6. Secondary Outcome:
Title Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic)
Description Assess occurrence of AESI: fractures (pathologic and non-pathologic).
Time Frame approximately 1 year and 8 months
Outcome Measure Data
Analysis Population Description
No analysis was performed. Outcome measure includes only number (%) of subjects with AESI.
 
Arm/Group TitleLead-in Enzalutamide Only (no Cycles)Lead-in Darolutamide Only (no Cycles)Lead-in Enzalutamide Followed by Radium-223/EnzalutamideLead-in Darolutamide Followed by Radium-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/Darolutamide
Arm/Group DescriptionLead-in Enzalutamide only. No Cycles.Lead-in Darolutamide only. No Cycles.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Radium-223 + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Radium-223 + Darolutamide.Randomized, Open-label Lead-in ARB (enzalutamide) followed by Placebo + Enzalutamide.Randomized, Open-label Lead-in ARB (darolutamide) followed by Placebo + Darolutamide.
Overall Number of Participants Analyzed11 10 4 4 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
0
0%
0
0%
1
25%
0
0%
0
0%
0
0%
Open or close this module Adverse Events
 
Time Frame Adverse event collection started at the time each subject signed informed consent and continued to be collected until each subject was 30 days post-last dose of study medication (enzalutamide, darolutamide, Ra-223, or placebo). The duration of the study was approximately 1 year and 8 months.
Adverse Event Reporting Description [Not specified]
 
Arm/Group Title 12 Weeks Lead-in Enzalutamide Only (No Cycles) 12 Weeks Lead-in Darolutamide Only (No Cycles) Lead-in Enzalutamide Followed by Ra-223/Enzalutamide Lead-in Darolutamide Followed by Ra-223/Darolutamide Lead-in Enzalutamide Followed by Placebo/Enzalutamide Lead-in Darolutamide Followed by Placebo/Darolutamide
Arm/Group Description 12 weeks of Lead-in Enzalutamide without any cycles 12 weeks of Lead-in Darolutamide without any cycles 12 weeks Lead-in Enzalutamide followed by up to 6 (once monthly) Ra-223 cycles + continued Enzalutamide 12 weeks Lead-in Darolutamide followed by up to 6 (once monthly) Ra-223 cycles + continued Darolutamide 12 weeks Lead-in Enzalutamide followed by up to 6 (once monthly) Placebo cycles + continued Enzalutamide 12 weeks Lead-in Darolutamide followed by up to 6 (once monthly) Placebo cycles + continued Darolutamide
All-Cause Mortality
  12 Weeks Lead-in Enzalutamide Only (No Cycles)12 Weeks Lead-in Darolutamide Only (No Cycles)Lead-in Enzalutamide Followed by Ra-223/EnzalutamideLead-in Darolutamide Followed by Ra-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/Darolutamide
 Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events
Total 1 / 4 (25%)0 / 3 (0%)0 / 4 (0%)1 / 4 (25%)0 / 3 (0%)0 / 3 (0%)
Serious Adverse Events
  12 Weeks Lead-in Enzalutamide Only (No Cycles)12 Weeks Lead-in Darolutamide Only (No Cycles)Lead-in Enzalutamide Followed by Ra-223/EnzalutamideLead-in Darolutamide Followed by Ra-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/Darolutamide
 Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events
Total 1 / 4 (25%)0 / 3 (0%)0 / 4 (0%)1 / 4 (25%)0 / 3 (0%)0 / 3 (0%)
Infections and infestations
Pneumonia † A [1] 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Respiratory, thoracic and mediastinal disorders
Hypoxia † A [1] 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Vascular disorders
Hypotension † A [1] 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Syncope † A [1] 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Indicates events were collected by systematic assessment.
ATerm from vocabulary, MedDRA 24.1
[1]SAE was not attributable to study treatments

Quality Control Review Comment provided by the National Library of Medicine:

  1. Information here appears inconsistent with information in other parts of the record.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
  12 Weeks Lead-in Enzalutamide Only (No Cycles)12 Weeks Lead-in Darolutamide Only (No Cycles)Lead-in Enzalutamide Followed by Ra-223/EnzalutamideLead-in Darolutamide Followed by Ra-223/DarolutamideLead-in Enzalutamide Followed by Placebo/EnzalutamideLead-in Darolutamide Followed by Placebo/Darolutamide
 Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events Affected / At Risk (%)# Events
Total 4 / 4 (100%)2 / 3 (66.67%)4 / 4 (100%)4 / 4 (100%)3 / 3 (100%)3 / 3 (100%)
Cardiac disorders
Atrial fibrillation † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Eye disorders
Cataract † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)20 / 3 (0%)00 / 3 (0%)0
Uveitis † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Vision blurred † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Gastrointestinal disorders
Constipation † A 2 / 4 (50%)20 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Diarrhoea † A 0 / 4 (0%)01 / 3 (33.33%)11 / 4 (25%)12 / 4 (50%)21 / 3 (33.33%)10 / 3 (0%)0
Dyspesia † A 0 / 4 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Nausea † A 0 / 4 (0%)02 / 3 (66.67%)21 / 4 (25%)11 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Vomiting † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
General disorders
Decreased appetite † A 0 / 4 (0%)00 / 3 (0%)01 / 4 (25%)10 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Fatigue † A 1 / 4 (25%)12 / 3 (66.67%)22 / 4 (50%)21 / 4 (25%)10 / 3 (0%)01 / 3 (33.33%)1
Gait disturbance † A 0 / 4 (0%)00 / 3 (0%)01 / 4 (25%)10 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Hot flush † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Infections and infestations
Corona virus infection † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Injury, poisoning and procedural complications
Concussion † A 0 / 4 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Contusion † A 0 / 4 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Fall † A 1 / 4 (25%)11 / 3 (33.33%)10 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Investigations
Neutrophil count decreased † A 0 / 4 (0%)00 / 3 (0%)01 / 4 (25%)10 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
White blood cell count decreased † A 0 / 4 (0%)00 / 3 (0%)01 / 4 (25%)10 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Metabolism and nutrition disorders
Diabetic complication † A 0 / 4 (0%)00 / 3 (0%)01 / 4 (25%)10 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Hypokalaemia † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)00 / 4 (0%)01 / 3 (33.33%)30 / 3 (0%)0
Musculoskeletal and connective tissue disorders
Arthralgia † A 0 / 4 (0%)01 / 3 (33.33%)10 / 4 (0%)01 / 4 (25%)11 / 3 (33.33%)11 / 3 (33.33%)1
Back Pain † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)01 / 3 (33.33%)1
Flank pain † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Muscle spasms † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)01 / 3 (33.33%)1
Musculoskeletal chest pain † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)01 / 3 (33.33%)1
Myalgia † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)00 / 4 (0%)01 / 3 (33.33%)10 / 3 (0%)0
Pain in extremity † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)00 / 4 (0%)01 / 3 (33.33%)10 / 3 (0%)0
Pain in jaw † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Rib fracture † A 0 / 4 (0%)00 / 3 (0%)01 / 4 (25%)10 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Spinal pain † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer Pain † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)01 / 3 (33.33%)1
Nervous system disorders
Confusional state † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)00 / 4 (0%)01 / 3 (33.33%)10 / 3 (0%)0
Dizziness † A 0 / 4 (0%)01 / 3 (33.33%)10 / 4 (0%)01 / 4 (25%)10 / 3 (0%)01 / 3 (33.33%)1
Headache † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Hypoaesthesia † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)00 / 4 (0%)01 / 3 (33.33%)11 / 3 (33.33%)2
Paraesthesia † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Peripheral sensory neuropathy † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)01 / 3 (33.33%)1
Restless legs syndrome † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)00 / 4 (0%)01 / 3 (33.33%)10 / 3 (0%)0
Taste disorder † A 0 / 4 (0%)00 / 3 (0%)01 / 4 (25%)10 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Psychiatric disorders
Confusional State † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Insomnia † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Renal and urinary disorders
Dysuria † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Pollakiuria † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Reproductive system and breast disorders
Hot flush † A 0 / 4 (0%)00 / 3 (0%)01 / 4 (25%)10 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Prostatic disorder † A 0 / 4 (0%)00 / 3 (0%)01 / 4 (25%)10 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Respiratory, thoracic and mediastinal disorders
Dyspnoea † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Nasopharyngitis † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Oropharyngeal pain † A 0 / 4 (0%)00 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Respiratory syncytial virus infection † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)00 / 4 (0%)00 / 3 (0%)00 / 3 (0%)0
Vascular disorders
Hypertension † A 1 / 4 (25%)10 / 3 (0%)00 / 4 (0%)01 / 4 (25%)10 / 3 (0%)00 / 3 (0%)0
Indicates events were collected by systematic assessment.
ATerm from vocabulary, MedDRA 24.1
Open or close this module Limitations and Caveats
ESCALATE (PC18-1005) was terminated early due to enrollment challenges.
Open or close this module More Information
Certain Agreements:
Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact:
Name/Official Title:
Penelope Manasco, CEO
Organization:
MANA RBM
Phone:
9195566456
Email:
pmanasco@manarbm.com

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