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

NCT04237584 | Terminated Phase 3 Results FDA Drug

• 1 other identifier: PC18-1005
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Castration-resistant Prostate Cancer

Keywords

mCRPC; ARB; Radiopharmaceutical

Outcome Measures

Primary Outcomes (1)

• Symptomatic Skeletal Event-free Survival (SSE-FS)

  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

  approximately 1 year and 8 months

Secondary Outcomes (5)

• Overall Survival (OS)

  approximately 1 year and 8 months

• Time to Chemotherapy Initiation

  approximately 1 year and 8 months

• Radiographic Progression-free Survival (rPFS)

  approximately 1 year and 8 months

• Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223.

  approximately 1 year and 8 months

• Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic)

  approximately 1 year and 8 months

Study Arms (6)

Enzalutamide during Lead-in Period

OTHER

Randomized, open-label lead-in ARB (enzalutamide tablets, 160 mg PO QD) for 12 weeks.

Drug: Enzalutamide during Lead-in Period

Lead-in Enzalutamide followed by Radium-223/Enzalutamide

ACTIVE COMPARATOR

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

Lead-in Enzalutamide followed by Placebo/Enzalutamide

PLACEBO COMPARATOR

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

Darolutamide during Lead-in Period

OTHER

Randomized, open-label lead-in ARB (darolutamide tablets, 300 mg PO BID) for 12 weeks.

Drug: Darolutamide during Lead-in Period

Lead-in Darolutamide followed by Radium-223/Darolutamide

ACTIVE COMPARATOR

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

Lead-in Darolutamide followed by Placebo/Darolutamide

PLACEBO COMPARATOR

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

Interventions

Enzalutamide during Lead-in Period DRUG

Participants will receive 12 weeks open-label lead-in ARB (enzalutamide) that will continue after double-blind randomization to radium-223 or placebo.

Also known as: Xtandi

Enzalutamide during Lead-in Period

Lead-in Enzalutamide followed by Radium-223/Enzalutamide DRUG

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.

Also known as: Xofigo, Xtandi

Lead-in Enzalutamide followed by Radium-223/Enzalutamide

Lead-in Enzalutamide followed by Placebo/Enzalutamide DRUG

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.

Also known as: Placebo, Xtandi

Lead-in Enzalutamide followed by Placebo/Enzalutamide

Darolutamide during Lead-in Period DRUG

Participants will receive 12 weeks open-label lead-in darolutamide that will continue after double-blind randomization to radium-223 or placebo.

Also known as: Nubeqa

Darolutamide during Lead-in Period

Lead-in Darolutamide followed by Radium-223/Darolutamide DRUG

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.

Also known as: Xofigo, Nubeqa

Lead-in Darolutamide followed by Radium-223/Darolutamide

Lead-in Darolutamide followed by Placebo/Darolutamide DRUG

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.

Also known as: Placebo, Nubeqa

Lead-in Darolutamide followed by Placebo/Darolutamide

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 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.
• 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.

Sponsors & Collaborators

• MANA RBM: lead
• Bayer: collaborator
• Carolina Urologic Research Center: collaborator
• Tulane University: collaborator
• Barbara Ann Karmanos Cancer Institute: collaborator

Study Sites (1)

Research Site

Myrtle Beach, South Carolina, 29572, United States

Location

MeSH Terms

Interventions

enzalutamide; radium Ra 223 dichloride; darolutamide

Limitations and Caveats

ESCALATE (PC18-1005) was terminated early due to enrollment challenges.

Results Point of Contact

• Title: Penelope Manasco, CEO
• Organization: MANA RBM

pmanasco@manarbm.com

9195566456

Study Officials

• Neal Shore, MD

  Carolina Urologic Research Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Masking of Radium-223 or placebo only
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 12 week lead-in open-label androgen-receptor blocker (ARB) followed by up to 6 cycles of double-blind Radium-223 or placebo.

Study Record Dates

• First Submitted: January 15, 2020
• First Posted: January 23, 2020
• Study Start: June 30, 2020
• Primary Completion: March 7, 2022
• Study Completion: March 7, 2022
• Last Updated: October 7, 2022
• Results First Posted: October 7, 2022

Record last verified: 2022-09

Locations

US (1)