Purpose

This study is designed to assess the antitumor efficacy and safety of pembrolizumab in combination with chemoradiotherapy (CRT) versus CRT alone in participants with muscle-invasive bladder cancer (MIBC). The primary hypothesis is that pembrolizumab + chemoradiotherapy is superior to placebo + chemoradiotherapy with respect to bladder intact event-free survival.

Condition

Eligibility

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

Inclusion Criteria

  • Has a histologically confirmed diagnosis of MIBC with predominant urothelial histology - Has clinically non-metastatic bladder cancer (N0M0) - Has planned and is eligible to receive chemoradiotherapy (CRT) and one of the protocol-specified radiosensitizing chemotherapy regimens - Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 - Demonstrates adequate organ function - Male participants are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of study intervention: - Refrain from donating sperm - Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception unless confirmed to be azoospermic - A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: - Is not a woman of childbearing potential (WOCBP) - Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 180 days after the last dose of study intervention; and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period

Exclusion Criteria

  • Has the presence of diffuse carcinoma in situ (CIS) (multiple foci of CIS) throughout the bladder - Has the presence of urothelial carcinoma (UC) at any site outside of the urinary bladder in the previous 2 years except for Ta stage/T1 stage/CIS of the upper tract if the participant has undergone a complete nephroureterectomy - Has a known additional malignancy that is progressing or has required active therapy within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or other carcinoma in situ that has undergone potentially curative therapy - Has the presence of bilateral hydronephrosis - Has limited bladder function with frequency of small amounts of urine (< 30 mL), urinary incontinence, or requires self-catheterization or a permanent indwelling catheter - Has received prior pelvic/local radiation therapy or any antineoplastic treatment for muscle-invasive bladder cancer (MIBC). Treatment for non-muscle invasive bladder cancer (NMIBC) with intravesical instillation therapy that was completed ≥28 days prior to randomization is allowed. Prior systemic treatment of NMIBC is not permitted. - Received prior therapy with an anti-PD-1 (programmed cell death protein 1), anti-PD-L1 (programmed death-ligand 1), or anti-PD-L2 (programmed cell death 1 ligand 2), or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4 [cytotoxic T-lymphocyte-associated protein 4], OX 40, or CD137 [cluster of differentiation 137]) - Has received a live vaccine within 30 days prior to the first dose of study drug - 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 intervention - Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or the selected chemotherapy regimen, and/or any of their excipients - Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug - Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed - Has a history of non-infectious pneumonitis that required steroids or has current pneumonitis - Has an active infection requiring systemic therapy - Has a known history of human immunodeficiency virus (HIV) infection - Has a known history of Hepatitis B or known active Hepatitis C virus infection - Has a known history of active tuberculosis (TB; Bacillus tuberculosis) - Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study - 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
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
All Sponsor personnel will be blinded to treatment assignments, with the exception of designated unblinded team members. Chemoradiotherapy will be administered to all participants and will be open-label.

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Pembrolizumab + Chemotherapy + Radiotherapy
Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.
  • Drug: Pembrolizumab
    400 mg of IV (intravenous) pembrolizumab once every 6 weeks.
    Other names:
    • MK-3475
    • KEYTRUDA®
  • Radiation: Conventional Radiotherapy (Bladder only)
    64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.
  • Radiation: Conventional Radiotherapy (Bladder and pelvic nodes)
    64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks.
  • Radiation: Hypofractionated Radiotherapy (Bladder only)
    55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.
  • Drug: Cisplatin
    35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.
  • Drug: Fluorouracil (5-FU)
    5-FU administered via IV infusion at a dose of 500 mg per cubic meter of body volume on Days 1-5 and 22-26.
  • Drug: Mitomycin C (MMC)
    MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.
  • Drug: Gemcitabine
    Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.
Placebo Comparator
Placebo + Chemotherapy + Radiotherapy
Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.
  • Radiation: Conventional Radiotherapy (Bladder only)
    64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.
  • Radiation: Conventional Radiotherapy (Bladder and pelvic nodes)
    64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks.
  • Radiation: Hypofractionated Radiotherapy (Bladder only)
    55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.
  • Drug: Cisplatin
    35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.
  • Drug: Fluorouracil (5-FU)
    5-FU administered via IV infusion at a dose of 500 mg per cubic meter of body volume on Days 1-5 and 22-26.
  • Drug: Mitomycin C (MMC)
    MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.
  • Drug: Gemcitabine
    Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.
  • Drug: Placebo to Pembrolizumab
    Placebo to intravenous (IV) pembrolizumab administered once every 6 weeks.

Recruiting Locations

Washington Cancer Institute at MedStar Washington Hospital Center ( Site 0041)
Washington, District of Columbia 20010
Contact:
Study Coordinator
443-831-7296

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.