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Study of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-3475-641/KEYNOTE-641)

NCT03834493

Description:

The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and enzalutamide in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC, are abiraterone-naïve, or are intolerant to or progressed on abiraterone acetate. There are two primary study hypotheses. Hypothesis 1: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Overall Survival (OS). Hypothesis 2: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Radiographic Progression-free Survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-3475-641/KEYNOTE-641)
  • Official Title: A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-641)

Clinical Trial IDs

  • ORG STUDY ID: 3475-641
  • SECONDARY ID: 2018-004117-40
  • SECONDARY ID: MK-3475-641
  • SECONDARY ID: KEYNOTE-641
  • SECONDARY ID: 195005
  • NCT ID: NCT03834493

Conditions

  • Prostatic Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA®, MK-3475Pembrolizumab + Enzalutamide
EnzalutamideXTANDI®Pembrolizumab + Enzalutamide
PlaceboNormal saline or dextrose infusionPlacebo + Enzalutamide

Purpose

The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and enzalutamide in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC, are abiraterone-naïve, or are intolerant to or progressed on abiraterone acetate. There are two primary study hypotheses. Hypothesis 1: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Overall Survival (OS). Hypothesis 2: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Radiographic Progression-free Survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review.

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + EnzalutamideExperimentalParticipants receive 200 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered orally (PO) once a day (QD) continuously until progression.
  • Pembrolizumab
  • Enzalutamide
Placebo + EnzalutamidePlacebo ComparatorParticipants receive placebo by IV infusion administered on Day 1 Q3W for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered PO QD continuously until progression.
  • Enzalutamide
  • Placebo

Eligibility Criteria

        Inclusion Criteria:

          -  Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without
             small cell histology

          -  Has prostate cancer progression while on androgen deprivation therapy (or post
             bilateral orchiectomy) within 6 months prior to randomization

          -  Has current evidence of metastatic disease documented by either bone lesions on bone
             scan and/or soft tissue disease by computed tomography/magnetic resonance imaging
             (CT/MRI)

          -  Is abiraterone-naive or are intolerant to/progressed on abiraterone

          -  Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM)

          -  Participants receiving bone resorptive therapy (including, but not limited to,
             bisphosphonate or denosumab) must have been on stable doses prior to randomization

          -  Participants must agree to the following during the study treatment period and for
             ≥120 days after the last dose of study treatment: Refrain from donating sperm PLUS Use
             contraception unless confirmed to be azoospermic (vasectomized or secondary to medical
             cause)

          -  Participants must agree to use male condom when engaging in any activity that allows
             for passage of ejaculate to another person of any sex

          -  Has provided newly obtained core or excisional biopsy (obtained within 12 months of
             screening) from soft tissue not previously irradiated (samples from tumors progressing
             in a prior site of radiation are allowed). Participants with bone only or bone
             predominant disease may provide a bone biopsy sample

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed
             within 7 days of randomization.

        Exclusion Criteria:

          -  Has a known additional malignancy that is progressing or has required active treatment
             in the last 3 years

          -  Has an active autoimmune disease that has required systemic treatment in past 2 years

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy

          -  Has undergone major surgery including local prostate intervention (excluding prostate
             biopsy) within 28 days prior to randomization and not recovered adequately from the
             toxicities and/or complications

          -  Has a gastrointestinal disorder affecting absorption or is unable to swallow
             tablets/capsules

          -  Has an active infection (including tuberculosis) requiring systemic therapy

          -  Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis

          -  Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or
             hepatitis C virus (HCV) infection

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis

          -  Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their
             excipients

          -  Has a history of seizure or any condition that may predispose to seizure

          -  Has a history of loss of consciousness within 12 months of screening

          -  Has hypotension (systolic blood pressure <86 millimeters of mercury [mmHg]) or
             uncontrolled hypertension (systolic blood pressure >170 mmHg or diastolic blood
             pressure >105 mmHg) at the screening visit

          -  Has bradycardia (heart rate of <50 beats per minute) on the screening
             electrocardiogram (ECG)

          -  Has history of prostate cancer progression on ketoconazole

          -  Has had prior treatment with enzalutamide, apalutamide, or darolutamide

          -  Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1),
             anti-programmed cell death-ligand 1 (anti-PD-L1), or anti PD-L2 agent or with an agent
             directed to another stimulatory or coinhibitory T-cell receptor

          -  Has received prior treatment with radium or other therapeutic radiopharmaceuticals for
             prostate cancer

          -  Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC

          -  Has had a prior anti-cancer monoclonal antibody (mAb) prior to randomization

          -  Has used herbal products that may have hormonal anti-prostate cancer activity and/or
             are known to decrease PSA levels (eg, saw palmetto) prior to randomization

          -  Has received a live vaccine within 30 days prior to randomization

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment

          -  Has a "superscan" bone scan

          -  Is expecting to conceive or father children within the projected duration of the
             study, starting with the screening visit through 120 days after the last dose of study
             treatment

          -  Has had an allogenic tissue/solid organ transplant
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Time from randomization to death due to any cause

Secondary Outcome Measures

Measure:Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Time from randomization to initiation of the first subsequent anti-cancer therapy or death, whichever occurs first
Measure:Prostate-specific Antigen (PSA) Response Rate
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Percentage of participants in the analysis population who have a negative change (decrease) in PSA level of ≥50% measured twice ≥3 weeks apart
Measure:Prostate-specific Antigen (PSA) Undetectable Rate
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Percentage of participants in the analysis population with PSA <0.2 ng/mL during study treatment
Measure:Objective Response Rate (ORR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Percentage of participants in the analysis population who have a best overall response of either confirmed Complete Response (CR) or a confirmed Partial Response (PR) per PCWG-modified RECIST 1.1
Measure:Duration of Response (DOR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Time from first documented evidence of confirmed Complete Response (CR) or Partial Response (PR) per PCWG-modified RECIST 1.1 until disease progression or death from any cause, whichever occurs first
Measure:Time to Prostate-specific Antigen (PSA) Progression
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Time from randomization to PSA progression. PSA progression date is defined as the date of 1) ≥25% increase and ≥2 ng/mL above the nadir, confirmed by a second value ≥3 weeks later if there is PSA decline from baseline, or 2) ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline
Measure:Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Time from randomization to radiographic soft tissue progression per PCWG-modified RECIST 1.1
Measure:Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("Worst Pain in 24 Hours") and Opiate Analgesic Use (Analgesic Quantification Algorithm [AQA] Score)
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Time from randomization to pain progression. In this study, pain progression will be assessed by participant responses to Item 3 of the BPI-SF and participant AQA Scores which are both assessed by participants daily for 7 consecutive days
Measure:Time to First Symptomatic Skeletal-related Event (SSRE)
Time Frame:Up to approximately 52 months
Safety Issue:
Description:Time from randomization to the first SSRE. SSRE is defined as radiation to prevent or relieve skeletal symptoms, occurrence of new symptomatic pathological fracture, spinal cord compression, or surgery to bone
Measure:Number of Participants Who Experience an Adverse Event (AE)
Time Frame:Up to approximately 52 months
Safety Issue:
Description:An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment
Measure:Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
Time Frame:Up to approximately 52 months
Safety Issue:
Description:The number of participants who discontinue study treatment due to an AE will be presented

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)

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