- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04237584
A Study Comparing ARB With Radium-223 vs ARB Therapy With Placebo and the Effect Upon Survival for mCRPC Patients (ESCALATE)
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
Study Overview
Status
Intervention / Treatment
- Drug: Enzalutamide during Lead-in Period
- Drug: Lead-in Enzalutamide followed by Radium-223/Enzalutamide
- Drug: Lead-in Enzalutamide followed by Placebo/Enzalutamide
- Drug: Darolutamide during Lead-in Period
- Drug: Lead-in Darolutamide followed by Radium-223/Darolutamide
- Drug: Lead-in Darolutamide followed by Placebo/Darolutamide
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
South Carolina
-
Myrtle Beach, South Carolina, United States, 29572
- Research Site
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Able and willing to provide informed consent.
- Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma.
- Men ≥ 18 years.
- ECOG performance status of 0 or 1 at screening.
- 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.
Patients must have progressive metastatic castration-resistant prostate cancer (mCRPC) at screening and on androgen deprivation therapy (ADT) as evidenced by either:
- 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);
- 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).
- For patients with disease progression manifested at nodal sites, irrespective of progression by rising PSA - progression defined per RECIST 1.1.
- Ongoing ADT with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy.
- 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.
Adequate bone marrow and organ function as defined by:
- Hemoglobin ≥ 10.0 g/dL
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelets ≥ 100 x 109/L
- Serum creatinine ≤ 1.95 mg/dL
- Estimated creatinine clearance >/= 30 mL/min by Cockroft-Gault calculation
- Alanine aminotransferase (ALT) ≤ 175 U/L
- Aspartate aminotransferase (AST) ≤ 100 U/L
- 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)
- LDH ≤ 224 U/L at screening.
- Albumin ≥ 2.5 g/dL
- 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.
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:
- Patients must have a documented ≥ 30% decline of PSA at any time during the 12 weeks of RT1.
- Patients must have no evidence of visceral metastatic disease at the time of RT2 randomization
- Ongoing treatment with RT1 and bone health agents at time of RT2 randomization.
- The treating site investigator deems RT2 (Ra-223 dichloride) treatment safe and feasible.
Exclusion Criteria:
- Pathological finding consistent with small cell carcinoma of the prostate.
- 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.
- 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).
- Prior treatment for more than 2 months with CYP17 inhibitors (e.g. abiraterone or orteronel).
- Prior treatment for more than 2 months with agents inhibiting androgen receptor signaling (e.g. enzalutamide, apalutamide, or darolutamide).
- Prior hemibody or whole-body external radiotherapy. Other types of prior external radiotherapy and brachytherapies are allowed.
- Prior therapy with radionuclides (e.g., radium-223, strontium-89, samarium-153, rhenium-186, rhenium-188, actinium-225 and lutetium-177).
- Current involvement in any drug or device trial involving investigational agent or medical device within the last 28 days prior to R1.
- 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.
- Hypersensitivity to compounds related to enzalutamide, darolutamide, or Ra-223.
- A blood transfusion ≤ 28 days prior to R1.
- Major surgical procedures ≤ 28 days or minor surgical procedures ≤7 days prior to R1. No waiting period is required following port-a-cath placement.
- 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.
- 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.
- 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.
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Sequential Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Enzalutamide during Lead-in Period
Randomized, open-label lead-in ARB (enzalutamide tablets, 160 mg PO QD) for 12 weeks.
|
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:
|
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.
|
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 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.
|
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:
|
Other: Darolutamide during Lead-in Period
Randomized, open-label lead-in ARB (darolutamide tablets, 300 mg PO BID) for 12 weeks.
|
Participants will receive 12 weeks open-label lead-in darolutamide that will continue after double-blind randomization to radium-223 or placebo.
Other Names:
|
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.
|
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 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.
|
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:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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:
|
approximately 1 year and 8 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall Survival (OS)
Time Frame: approximately 1 year and 8 months
|
Number of subjects who survived between RT2 randomization through data cut-off.
|
approximately 1 year and 8 months
|
Time to Chemotherapy Initiation
Time Frame: approximately 1 year and 8 months
|
Number of subjects who began docetaxel or cabazitaxel treatment during the study.
|
approximately 1 year and 8 months
|
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.
|
approximately 1 year and 8 months
|
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.
|
approximately 1 year and 8 months
|
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).
|
approximately 1 year and 8 months
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Chair: Neal Shore, MD, Carolina Urologic Research Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- PC18-1005
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Metastatic Castration-resistant Prostate Cancer
-
Myovant Sciences GmbHRecruitingMetastatic Castration-Resistant Prostate Cancer | Metastatic Castration-Sensitive Prostate Cancer | Non-Metastatic Castration-Resistant Prostate CancerUnited States
-
Janux TherapeuticsRecruitingProstate Cancer | Metastatic Castration-resistant Prostate Cancer | Castration Resistant Prostatic CancerUnited States, Australia
-
Universität des SaarlandesRecruitingProstate Cancer Metastatic | Advanced Prostate Carcinoma | Castration Resistant Prostatic CancerGermany
-
Vadim S KoshkinEli Lilly and Company; Prostate Cancer FoundationActive, not recruitingCastration-Resistant Prostate Carcinoma | Stage IV Prostate Cancer AJCC v8 | Stage IVA Prostate Cancer AJCC v8 | Stage IVB Prostate Cancer AJCC v8 | Metastatic Castration-resistant Prostate Cancer | Metastatic Prostate Adenocarcinoma | Metastatic Castration-resistant Prostate CarcinomaUnited States
-
Massachusetts General HospitalBayerCompletedProstate Cancer | Castration-resistant Prostate Cancer | Castration-resistant Prostate Cancer Metastatic to BoneUnited States
-
Sidney Kimmel Comprehensive Cancer Center at Johns...Clarus TherapeuticsRecruitingProstate Cancer | Castration-resistant Prostate Cancer | Metastatic Castration-resistant Prostate CancerUnited States
-
Rohan GarjeJanssen Scientific Affairs, LLCNot yet recruitingCastration-resistant Prostate Cancer | Metastatic Prostate Cancer | Metastatic Castration-resistant Prostate CancerUnited States
-
BAMF HealthRecruitingMetastatic Castration-resistant Prostate CancerUnited States
-
Chia Tai Tianqing Pharmaceutical Group Co., Ltd.RecruitingMetastatic Castration-resistant Prostate CancerChina
-
Hinova Pharmaceuticals Inc.CompletedMetastatic Castration Resistant Prostate CancerChina
Clinical Trials on Enzalutamide during Lead-in Period
-
Ramsay Générale de SantéGCS Ramsay Santé pour l'Enseignement et la RechercheRecruitingVirtual Reality | Cancer of ColonFrance
-
Hôpital RothschildCompletedHealth Knowledge, Attitudes, PracticeFrance
-
Institut Claudius RegaudCompleted
-
Peter J PughUnknown
-
Centre Hospitalier Annecy GenevoisWithdrawnCognition Disorders | Fall Injury | Dependence | Fall From Bed | Fall in Nursing HomeFrance
-
Augusta UniversityRecruitingSpinal Cord Stimulator Trial Period, Neuromodulation Trial Period, SCS Trial PeriodUnited States
-
StemCells, Inc.CompletedPelizaeus-Merzbacher Disease | PMDUnited States
-
Thomas Jefferson UniversityEli Lilly and CompanyTerminatedMigraineUnited States
-
Schuechtermann-KlinikMedtronicUnknownHeart Failure | Left Bundle-Branch BlockGermany
-
Taro Iguchi, MD, PHDBayer Yakuhin, Ltd.Active, not recruitingBone Metastases | Castration-resistant Prostate CancerJapan