Clinical Trials /

Perioperative Pembrolizumab (MK-3475) Plus Cystectomy Versus Cystectomy Alone in Cisplatin-ineligible Participants With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905)

NCT03924895

Description:

A global, randomized phase III study to evaluate perioperative pembrolizumab with radical cystectomy + pelvic lymph node dissection (RC+PLND) versus RC+PLND alone in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC).

Related Conditions:
  • Bladder Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Perioperative Pembrolizumab (MK-3475) Plus Cystectomy Versus Cystectomy Alone in Cisplatin-ineligible Participants With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905)
  • Official Title: A Phase 3 Randomized Study of Cystectomy Plus Perioperative Pembrolizumab Versus Cystectomy Alone in Cisplatin-ineligible Participants With Muscle-invasive Bladder Cancer (KEYNOTE-905)

Clinical Trial IDs

  • ORG STUDY ID: 3475-905
  • SECONDARY ID: MK-3475-905
  • SECONDARY ID: 2018-003809-26
  • SECONDARY ID: KEYNOTE-905
  • NCT ID: NCT03924895

Conditions

  • Urinary Bladder Cancer, Muscle-invasive

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA®, MK-3475Pembrolizumab + Surgery

Purpose

A global, randomized phase III study to evaluate perioperative pembrolizumab with radical cystectomy + pelvic lymph node dissection (RC+PLND) versus RC+PLND alone in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC).

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + SurgeryExperimentalParticipants receive 3 preoperative cycles of pembrolizumab, followed by standard of care surgery, followed by up to 14 cycles of postoperative pembrolizumab.
  • Pembrolizumab
Surgery aloneActive ComparatorParticipants receive standard of care surgery alone.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with
                 predominant (≥50%) urothelial histology. Participants with mixed histology are
                 eligible provided the urothelial component is ≥50%. Urothelial carcinomas not
                 originating from the bladder are not eligible. Participants whose tumors contain any
                 neuroendocrine component are not eligible.
    
              -  Clinically non-metastatic bladder cancer determined by imaging
    
              -  Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND ), and
                 agreement to undergo curative intent standard RC + PLND (including prostatectomy if
                 applicable)
    
              -  Ineligible for treatment with cisplatin, as defined by meeting at least one of the
                 following criteria:
    
                   -  Impaired renal function with measured or calculated CrCl 30 to 59 mL/min
    
                   -  Eastern Cooperative Oncology Group (ECOG) Performance Status 2
    
                   -  Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometric
                      hearing loss
    
                   -  CTCAE v.4 Grade ≥2 peripheral neuropathy
    
                   -  New York Heart Association (NYHA) Class III heart failure
    
              -  Transurethral resection (TUR) of a bladder tumor that is submitted and adequate for
                 evaluation of histology, muscle invasion and PD-L1 status
    
              -  ECOG performance status of 0, 1, or 2
    
              -  Adequate organ function
    
            Exclusion Criteria:
    
              -  Known additional non-urothelial malignancy that is progressing or has required active
                 treatment ≤3 years of study randomization, with certain exceptions
    
              -  Received any prior systemic anti-neoplastic treatment for muscle-invasive bladder
                 cancer (MIBC)
    
              -  Received prior therapy with a anti-programmed cell death protein 1 (PD-1),
                 anti-programmed death-ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2
                 (PD-L2), or with an agent directed to another stimulatory or co-inhibitory T-cell
                 receptor
    
              -  Received prior systemic anti-cancer therapy including investigational agents within 3
                 years prior to randomization
    
              -  Received any prior radiotherapy to the bladder
    
              -  Received a live vaccine within 30 days prior to the first dose of study drug
    
              -  Current participation in or participation in a study of an investigational agent or
                 use of an investigational device within 4 weeks prior to the first dose of study
                 intervention
    
              -  Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or any
                 other form of immunosuppressive therapy within 7 days prior the first dose of study
                 drug
    
              -  Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of
                 their excipients
    
              -  Active autoimmune disease that has required systemic therapy in past 2 years (i.e.,
                 with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
                 Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
                 replacement therapy for adrenal or pituitary insufficiency) is not considered a form
                 of systemic therapy and is allowed.
    
              -  History of (non-infectious) pneumonitis that required steroids, or current
                 pneumonitis.
    
              -  Active infection requiring systemic therapy
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Pathologic Complete Response (pCR) Rate in All Participants
    Time Frame:Up to approximately 3 months (Time of surgery)
    Safety Issue:
    Description:Pathologic complete response rate is defined as the percentage of participants having pCR. pCR is defined as absence of viable tumor (pT0) in examined tissue from RC and PLND, as determined centrally.

    Secondary Outcome Measures

    Measure:Overall Survival (OS) in All Participants
    Time Frame:Up to approximately 6.5 years
    Safety Issue:
    Description:OS is defined as the time from randomization to death due to any cause.
    Measure:Overall Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
    Time Frame:Up to approximately 6.5 years
    Safety Issue:
    Description:OS is defined as the time from randomization to death due to any cause.
    Measure:Disease-Free Survival (DFS) in All Participants
    Time Frame:Up to approximately 5.5 years
    Safety Issue:
    Description:DFS is defined as the time from first post-surgery baseline scan until: local or distant recurrence as assessed by imaging (BICR) and/or biopsy Death due to any cause
    Measure:Disease-Free Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
    Time Frame:Up to approximately 5.5 years
    Safety Issue:
    Description:DFS is defined as the time from first post-surgery baseline scan until: local or distant recurrence as assessed by imaging (BICR) and/or biopsy Death due to any cause
    Measure:Pathologic Downstaging (pDS) Rate in All Participants
    Time Frame:Up to approximately 3 months (Time of surgery)
    Safety Issue:
    Description:Pathologic downstaging rate is defined as the percentage of participants having pDS. pDS is defined as participants with a tumor classification of <pT2 (includes pT0, pTis, pTa, pT1) and N0 in examined tissue from RC and PLND.
    Measure:Pathologic Downstaging (pDS) Rate in Participants Whose Tumors Express PD-L1, CPS ≥10
    Time Frame:Up to approximately 3 months (Time of surgery)
    Safety Issue:
    Description:Pathologic downstaging rate is defined as the percentage of participants having pDS. pDS is defined as participants with a tumor classification of <pT2 (includes pT0, pTis, pTa, pT1) and N0 in examined tissue from RC and PLND.
    Measure:Number of Participants Experiencing Adverse Events (AEs)
    Time Frame:Up to approximately 6.5 years
    Safety Issue:
    Description:An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
    Measure:Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs)
    Time Frame:Up to approximately 1 year
    Safety Issue:
    Description:An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
    Measure:Number of Participants Experiencing Perioperative Complications
    Time Frame:Up to approximately 1 year
    Safety Issue:
    Description:The number of participants who experience perioperative complications 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)
    • Pembrolizumab (MK-3475)

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