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A Study Comparing ARB With Radium-223 vs ARB Therapy With Placebo and the Effect Upon Survival for mCRPC Patients (ESCALATE)

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ClinicalTrials.gov Identifier: NCT04237584
Recruitment Status : Recruiting
First Posted : January 23, 2020
Last Update Posted : July 17, 2020
Sponsor:
Collaborators:
Bayer
Carolina Urologic Research Center
Tulane University
Barbara Ann Karmanos Cancer Institute
Information provided by (Responsible Party):
MANA RBM

Tracking Information
First Submitted Date  ICMJE January 15, 2020
First Posted Date  ICMJE January 23, 2020
Last Update Posted Date July 17, 2020
Actual Study Start Date  ICMJE June 30, 2020
Estimated Primary Completion Date September 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 21, 2020)
Symptomatic skeletal event-free survival (SSE-FS) [ Time Frame: through study completion, an average of 5 years ]
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 21, 2020)
  • Overall survival (OS) [ Time Frame: through study completion, an average of 5 years ]
  • Time to chemotherapy initiation [ Time Frame: through study completion, an average of 5 years ]
  • Radiographic progression-free survival (rPFS) [ Time Frame: through study completion, an average of 5 years ]
  • Safety profile of androgen receptor blocker (ARB) therapy with or without radium-223; number of participants with treatment-related adverse events as assessed by CTCAE v5.0. [ Time Frame: through study completion, an average of 5 years ]
  • Occurrence of AESI: bone fractures (pathologic and non-pathologic) [ Time Frame: through study completion, an average of 5 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study Comparing ARB With Radium-223 vs ARB Therapy With Placebo and the Effect Upon Survival for mCRPC Patients
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Lead-in open-label androgen-receptor blocker (ARB) followed by double-blind Radium-223 or placebo.
Masking: Double (Participant, Investigator)
Masking Description:
Masking of Radium-223 or placebo only
Primary Purpose: Treatment
Condition  ICMJE Metastatic Castration-resistant Prostate Cancer
Intervention  ICMJE
  • Drug: Darolutamide
    Participants will be randomly assigned to 12 weeks lead-in ARB (darolutamide or enzalutamide) that will continue after double-blind randomization to radium-223 or placebo.
    Other Name: Nubeqa
  • Drug: Enzalutamide
    Participants will be randomly assigned to 12 weeks lead-in ARB (darolutamide or enzalutamide) that will continue after double-blind randomization to radium-223 or placebo.
    Other Name: Xtandi
  • Drug: Radium-223
    After a 12-week lead-in period of open-label ARB, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label ARB.
    Other Name: Xofigo
  • Other: Placebo
    After a 12-week lead-in period of open-label ARB, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label ARB.
    Other Name: Saline solution
Study Arms  ICMJE
  • Active Comparator: Lead-in ARB followed by Radium-223/ARB
    Randomized, Open-label Lead-in ARB (Enzalutamide or Darolutamide) followed by Radium-223 + ARB.
    Interventions:
    • Drug: Darolutamide
    • Drug: Enzalutamide
    • Drug: Radium-223
  • Placebo Comparator: Lead-in ARB followed by Placebo/ARB
    Randomized, Open-label Lead-in ARB (Enzalutamide or Darolutamide) followed by Placebo + ARB.
    Interventions:
    • Drug: Darolutamide
    • Drug: Enzalutamide
    • Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 21, 2020)
499
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2024
Estimated Primary Completion Date September 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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."
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Penelope K Manasco, MD (919) 556-9456 pmanasco@manarbm.com
Contact: Study Help Desk (855) 704-0476 Help@manarbm.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04237584
Other Study ID Numbers  ICMJE PC18-1005
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party MANA RBM
Study Sponsor  ICMJE MANA RBM
Collaborators  ICMJE
  • Bayer
  • Carolina Urologic Research Center
  • Tulane University
  • Barbara Ann Karmanos Cancer Institute
Investigators  ICMJE
Study Chair: Neal Shore, MD Carolina Urologic Research Center
PRS Account MANA RBM
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP