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).

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Histologically confirmed diagnosis of muscle-invasive bladder cancer (MIBC) cT2-T4aN0M0 or cT1-T4aN1M0 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 show any of the following variant histologies are not eligible: plasmacytoid, clear cell, lipid rich, giant cell, sarcomatoid, and/or neuroendocrine component.
  • 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
  • New York Heart Association (NYHA) Class III heart failure
  • Transurethral resection (TUR) of a bladder tumor that is submitted and adequate to determine determine pathologic stage pT2-T4a or pT1, urothelial histology, and PD-L1 status. For confirmation of stages T2-T4a, TUR biopsy samples must include detrusor muscle.
  • 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 120 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 60 days after the last dose of enfortumab vedotin. 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 treatment ≤3 years of study randomization, with certain exceptions
  • ≥ N2 or M1 disease
  • Received any prior systemic antineoplastic treatment for muscle-invasive bladder cancer (MIBC)
  • 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 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
  • 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 (≥ Grade 3) hypersensitivity to any enfortumab vedotin 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

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Pembrolizumab + Surgery
Participants receive 3 preoperative cycles of pembrolizumab, followed by standard of care surgery, followed by 14 cycles of postoperative pembrolizumab. Each cycle is 21 days.
  • Drug: Pembrolizumab
    Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.
    Other names:
    • KEYTRUDA®
    • MK-3475
  • Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
    Surgical RC+PLND will be done in accordance with the American Urological Association (AUA)/American Society of Clinical Oncology (ASCO)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO) guidelines.
  • Drug: Enfortumab Vedotin
    Enfortumab vedotin 1.25 mg/kg by intravenous (IV) infusion, given on Days 1 and 8 of each 21-day cycle.
    Other names:
    • Padcev
    • ASG-22CE
    • ASG-22ME
Active Comparator
Surgery alone
Participants receive standard of care surgery alone.
  • Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
    Surgical RC+PLND will be done in accordance with the American Urological Association (AUA)/American Society of Clinical Oncology (ASCO)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO) guidelines.
Experimental
Enfortumab Vedotin + Pembrolizumab + Surgery
Participants 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.
  • Drug: Enfortumab Vedotin
    Enfortumab vedotin 1.25 mg/kg by intravenous (IV) infusion, given on Days 1 and 8 of each 21-day cycle.
    Other names:
    • Padcev
    • ASG-22CE
    • ASG-22ME

Recruiting Locations

Georgetown University Medical Center ( Site 0022)
Washington, District of Columbia 20007
Contact:
Study Coordinator
202-444-2198

More Details

Status
Recruiting
Sponsor
Merck Sharp & Dohme Corp.

Study Contact

Toll Free Number
1-888-577-8839
Trialsites@merck.com

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.