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Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Cisplatin-ineligible Participants With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)

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 Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Cisplatin-ineligible Participants With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)
  • Official Title: A Randomized Phase 3 Study Evaluating Cystectomy With Perioperative Pembrolizumab and Cystectomy With Perioperative Enfortumab Vedotin and Pembrolizumab Versus Cystectomy Alone in Cisplatin-Ineligible Participants With Muscle-Invasive Bladder Cancer (KEYNOTE-905/EV-303)

Clinical Trial IDs

  • ORG STUDY ID: 3475-905
  • SECONDARY ID: MK-3475-905
  • SECONDARY ID: 2018-003809-26
  • SECONDARY ID: KEYNOTE-905
  • SECONDARY ID: EV-303
  • NCT ID: NCT03924895

Conditions

  • Urinary Bladder Cancer, Muscle-invasive

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA®, MK-3475Pembrolizumab + Surgery
Enfortumab VedotinPadcev, ASG-22CE, ASG-22MEEnfortumab Vedotin + Pembrolizumab + 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 14 cycles of postoperative pembrolizumab. Each cycle is 21 days.
  • Pembrolizumab
Surgery aloneActive ComparatorParticipants receive standard of care surgery alone.
    Enfortumab Vedotin + Pembrolizumab + SurgeryExperimentalParticipants receive 3 preoperative cycles of enfortumab vedotin + pembrolizumab, followed by standard of care surgery, followed by 6 cycles of postoperative enfortumab vedotin + pembrolizumab, followed by 8 cycles of pembrolizumab alone. Each cycle is 21 days.
    • Enfortumab Vedotin

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Have a histologically confirmed diagnosis of urothelial carcinoma (cT2-T4aN0M0 or
                 T1-T4aN1M0) with predominant (≥50%) urothelial histology and programmed cell death
                 ligand 1 (PD-L1) expression assessment to be confirmed by Blinded Independent Central
                 Review (BICR) (central pathology and/or imaging).
    
              -  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 creatinine clearance (CrCl)
                      30 to 59 mL/min (calculated by Cockcroft-Gault method, Modification of Diet of
                      Renal Disease [MDRD] equations, or measured by 24-hour urine collection)
    
                   -  Eastern Cooperative Oncology Group (ECOG) Performance Status 2
    
                   -  Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometric
                      hearing loss
    
                   -  New York Heart Association (NYHA) Class III heart failure
    
              -  Transurethral resection (TUR) of a bladder tumor that is submitted for central
                 pathology assessment and adequate to determine urothelial histology and PD-L1
                 expression assessment.
    
              -  ECOG performance status of 0, 1, or 2
    
              -  Adequate organ function
    
              -  A male participant is eligible to participate if he agrees to use contraception and
                 refrain from donating sperm during the intervention period and for at least 180 days
                 after the last dose of enfortumab vedotin. If the male participants are receiving
                 pembrolizumab only or undergoing surgery only, there are no contraception
                 requirements.
    
              -  A female participant is eligible to participate if she is not pregnant, not
                 breastfeeding, and at least 1 of the following conditions applies: Not a (woman of
                 childbearing potential) WOCBP or a WOCBP who agrees to use a highly effective
                 contraceptive method or be abstinent from heterosexual intercourse (as their preferred
                 and usual lifestyle) during the intervention period and for at least 120 days after
                 the last dose of pembrolizumab and at least 180 days after the last dose of enfortumab
                 vedotin; whichever comes last. A female participant must agree not to donate eggs
                 during this period as well.
    
              -  A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before
                 the first dose of study intervention.
    
            Exclusion Criteria:
    
              -  Known additional non-urothelial malignancy that is progressing or has required active
                 anticancer treatment ≤3 years of study randomization, with certain exceptions
    
              -  Has ≥ N2 or metastatic disease (M1) as identified by imaging
    
              -  Received any prior systemic treatment, chemoradiation, and/or radiation therapy for
                 for muscle-invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer
                 (NMIBC)
    
              -  Received prior therapy with an 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 anticancer therapy including investigational agents within 3
                 years prior to randomization
    
              -  Received any prior radiotherapy to the bladder
    
              -  Received a partial cystectomy of the bladder to remove any non-muscle-invasive bladder
                 cancer (NMIBC) or MIBC
    
              -  Received a live vaccine within 30 days prior to the first dose of study intervention
    
              -  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
    
              -  Ongoing sensory or motor neuropathy Grade 2 or higher
    
              -  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. Physiologic replacement doses of corticosteroids are permitted for participants
                 with adrenal insufficiency.
    
              -  Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of
                 their excipients
    
              -  Severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient contained
                 in the drug formulation of enfortumab vedotin
    
              -  Active keratitis or corneal ulcerations. Participants with superficial punctate
                 keratitis are allowed if the disorder is being adequately treated in the opinion of
                 the investigator.
    
              -  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 uncontrolled diabetes
    
              -  History of (noninfectious) pneumonitis that required steroids, or current pneumonitis.
    
              -  Active infection requiring systemic therapy
    
              -  Has had an allogenic tissue/solid organ transplant
          
    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 (pT0N0) 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 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 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)

    Last Updated

    April 23, 2021