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NCT03244384 · CITED IN SOURCE DOCUMENTS

Testing MK-3475 (Pembrolizumab) After Surgery for Localized Muscle-Invasive Bladder Cancer and Locally Advanced Urothelial Cancer

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
ACTIVE NOT RECRUITING
Registry last update
2026-08-28

This phase III trial studies how well pembrolizumab works in treating patients with bladder cancer that has spread into the deep muscle of the bladder wall (muscle-invasive) or urothelial cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced). Monoclonal antibodies recognizing and blocking checkpoint molecules can enhance the patient's immune response and therefore help fight cancer. Pembrolizumab is one of the monoclonal antibodies that block the PD-1 axis and can interfere with the ability of tumor cells to grow.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
eligibility Criteria
Inclusion Criteria: * PRE-REGISTRATION ELIGIBILITY CRITERIA * Histologically confirmed muscle-invasive urothelial carcinoma of the bladder, urethra, upper tract, or lymph node positive (LN+) disease; variant histology allowed as long as urothelial carcinoma is predominant (any amount of squamous differentiation is allowed); any component of neuroendocrine carcinoma is excluded * Paraffin tissue samples obtained by transurethral resection of muscle-invasive bladder tumor, upper tract resection, or radical cystectomy/nephrectomy/ureterectomy/nephroureterectomy/cystoprostatectomy or urethrectomy must be available; this specimen submission is mandatory prior to registration as results will be used for stratification; specimens from radical/definitive surgery (radical cystectomy/nephrectomy/ureterectomy /nephroureterectomy/cystoprostatectomy and LN dissection) are preferred over transurethral resection, if available * Patient must fit into one of the following three categories: * Patients who received neoadjuvant chemotherapy and pathologic stage at surgical resection is \>= pT2 and/or N+ OR * Patients who are not cisplatin-eligible (according to \>= 1 of the following criteria: Eastern Cooperative Oncology Group \[ECOG\] performance status of 2, creatinine clearance \< 60 mL/min, grade \>= 2 hearing loss, grade \>= 2 neuropathy, or New York Heart Association class III heart failure and pathologic stage at surgical resection is \>= pT3 or pN+) OR * Patients that decline adjuvant cisplatin-based or other systemic chemotherapy based on an informed discussion with the physician and pathologic stage at surgical resection is \>= pT3 or pN+ * The 7th edition of American Joint Committee on Cancer (AJCC) staging will be utilized; patient must have had radical cystectomy (cystoprostatectomy for men) and lymph node dissection (for bladder primary), or nephrectomy, nephroureterectomy or ureterectomy (for uppertract tumors) or urethrectomy (in addition to a radical cystectomy-either simultaneously or in the past) \>= 4 weeks but =\< 16 weeks prior to pre-registration; patients who have had a partial cystectomy as definitive therapy are not eligible * No gross cancer at the surgical margins; microscopic invasive urothelial carcinoma positive margins are allowed; carcinoma in situ (CIS) at margins is considered negative margins * No evidence of residual cancer or metastasis after surgery; patients with upper tract urothelial carcinoma must have a negative cystoscopy within 3 months prior to pre-registration; if the bladder has been removed a cystoscopy is not required * No metastatic disease (or radiologic findings "concerning" for metastatic disease) on cross-sectional imaging (according to Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]1.1 criteria) * No active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease; human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible * No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years * Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible * Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible * No known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected) * No live vaccine within 30 days prior to the first dose of study drug; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed * No postoperative/adjuvant systemic therapy * No prior treatment with any therapy on the PD-1/PD-L1 axis * No treatment with any other type of investigational agent =\< 4 weeks before pre-registration * No major surgery =\< 4 weeks before pre-registration * No radiation therapy =\< 4 weeks before pre-registration * No neoadjuvant chemotherapy =\< 4 weeks before pre-registration * Not currently requiring hemodialysis * Age \>= 18 years * Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown * ECOG performance status =\< 2 * Absolute neutrophil count (ANC) \>= 1,200/mm\^3 * Leukocytes \>= 3,000/ mm\^3 * Platelet count \>= 75,000/mm\^3 * Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L * Total bilirubin =\< 1.5 x upper limit of normal (ULN) * Bilirubin for patients with Gilbert's =\< 3.0 x ULN * Calculated (calc.) creatinine clearance \>= 30 mL/min (using either Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation or Cockcroft-Gault formula) * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 3.0 x upper limit of normal (ULN) * Serum albumin \>= 2.8 g/dL * For women of childbearing potential only: a negative urine or serum pregnancy test done =\< 7 days prior to pre-registration is required * REGISTRATION ELIGIBILITY CRITERIA: Results of central PD-L1 testing available; Q2 Solutions will forward the PD-L1 results to the statistical center and the statistical center will notify the site that the result is available; since the results with be blinded to the site the notification from the Alliance registration/randomization office will serve as a confirmation of this eligibility criteria; after sites receive the confirmation e-mail from Alliance they can register the patient
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, CT urography, and/or MRI throughout the trial. Patients may also undergo a cystoscopy and blood sample collection during screening and on study.
    intervention Names
    1. Procedure: Biospecimen Collection
    2. Procedure: Computed Tomography
    3. Procedure: CT Urography
    4. Procedure: Cystoscopy
    5. Procedure: Magnetic Resonance Imaging
    6. Biological: Pembrolizumab
    7. Other: Pharmacological Study
    8. Other: Quality-of-Life Assessment
    9. Other: Questionnaire Administration
    label
    Arm A (pembrolizumab)
    type
    EXPERIMENTAL
  2. description
    Patients undergo observation. Patients undergo a CT scan, CT urography, and/or MRI throughout the trial. Patients may also undergo a cystoscopy and blood sample collection during screening and on study.
    intervention Names
    1. Procedure: Biospecimen Collection
    2. Other: Clinical Observation
    3. Procedure: Computed Tomography
    4. Procedure: CT Urography
    5. Procedure: Cystoscopy
    6. Procedure: Magnetic Resonance Imaging
    7. Other: Pharmacological Study
    8. Other: Quality-of-Life Assessment
    9. Other: Questionnaire Administration
    label
    Arm B (observation)
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. Arm A (pembrolizumab)
    2. Arm B (observation)
    description
    Undergo blood sample collection
    name
    Biospecimen Collection
    other Names
    1. Biological Sample Collection
    2. Biospecimen Collected
    3. Sample Collection
    4. Specimen Collection
    type
    PROCEDURE
  2. arm Group Labels
    1. Arm B (observation)
    description
    Undergo observation
    name
    Clinical Observation
    other Names
    1. observation
    type
    OTHER
  3. arm Group Labels
    1. Arm A (pembrolizumab)
    2. Arm B (observation)
    description
    Undergo a CT scan
    name
    Computed Tomography
    other Names
    1. CAT
    2. CAT Scan
    3. Computed Axial Tomography
    4. Computerized Axial Tomography
    5. Computerized axial tomography (procedure)
    6. Computerized Tomography
    7. Computerized Tomography (CT) scan
    8. CT
    9. CT Scan
    10. Diagnostic CAT Scan
    11. Diagnostic CAT Scan Service Type
    12. tomography
    type
    PROCEDURE
  4. arm Group Labels
    1. Arm A (pembrolizumab)
    2. Arm B (observation)
    description
    Undergo a CT urography
    name
    CT Urography
    other Names
    1. Urography Computed Tomography
    type
    PROCEDURE
  5. arm Group Labels
    1. Arm A (pembrolizumab)
    2. Arm B (observation)
    description
    Undergo a cystoscopy
    name
    Cystoscopy
    other Names
    1. CS
    type
    PROCEDURE
  6. arm Group Labels
    1. Arm A (pembrolizumab)
    2. Arm B (observation)
    description
    Undergo a MRI
    name
    Magnetic Resonance Imaging
    other Names
    1. Magnetic Resonance
    2. Magnetic Resonance Imaging (MRI)
    3. Magnetic resonance imaging (procedure)
    4. Magnetic Resonance Imaging Scan
    5. Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    6. MR
    7. MR Imaging
    8. MRI
    9. MRI Scan
    10. MRIs
    11. NMR Imaging
    12. NMRI
    type
    PROCEDURE
  7. arm Group Labels
    1. Arm A (pembrolizumab)
    description
    Given IV
    name
    Pembrolizumab
    other Names
    1. BCD-201
    2. GME 751
    3. GME751
    4. Keytruda
    5. Lambrolizumab
    6. MK 3475
    7. MK-3475
    8. MK3475
    9. Pembrolizumab Biosimilar BCD-201
    10. Pembrolizumab Biosimilar GME751
    11. Pembrolizumab Biosimilar QL2107
    12. Pembrolizumab Biosimilar RPH-075
    type
    BIOLOGICAL
  8. arm Group Labels
    1. Arm A (pembrolizumab)
    2. Arm B (observation)
    description
    Correlative studies
    name
    Pharmacological Study
    type
    OTHER
  9. arm Group Labels
    1. Arm A (pembrolizumab)
    2. Arm B (observation)
    description
    Ancillary studies
    name
    Quality-of-Life Assessment
    other Names
    1. Quality of Life Assessment
    type
    OTHER
  10. arm Group Labels
    1. Arm A (pembrolizumab)
    2. Arm B (observation)
    description
    Ancillary studies
    name
    Questionnaire Administration
    type
    OTHER
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
739
type
ESTIMATED
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    The stratified proportional hazards model will be the primary analysis. The hazard ratio and its 95% confidence interval from the stratified Cox model with a single treatment covariate will be reported. The unstratified hazard ratio will also be presented.
    measure
    Overall survival
    time Frame
    From randomization to the date of death from any cause, assessed up to 5 years
  2. description
    The stratified proportional hazards model will be the primary analysis. The hazard ratio and its 95% confidence interval from the stratified Cox model with a single treatment covariate will be reported. The unstratified hazard ratio will also be presented.
    measure
    Disease-free survival
    time Frame
    From randomization to the first metastatic recurrence (presence of any recurrent disease), or death, whichever occurs first, assessed up to 5 years
secondary Outcomes
  1. description
    The stratified proportional hazards model will be the primary analysis. The hazard ratio and its 95% confidence interval from the stratified Cox model with a single treatment covariate will be reported. The unstratified hazard ratio will also be presented.
    measure
    Overall survival in PD-L1 positive and negative patients
    time Frame
    From randomization to the date of death from any cause, assessed up to 5 years
  2. description
    The stratified proportional hazards model will be the primary analysis. The hazard ratio and its 95% confidence interval from the stratified Cox model with a single treatment covariate will be reported. The unstratified hazard ratio will also be presented.
    measure
    Disease-free survival in PD-L1 positive and negative patients
    time Frame
    From randomization to the first metastatic recurrence (presence of any recurrent disease), or death, whichever occurs first, assessed up to 5 years
Full study description
brief Summary
This phase III trial studies how well pembrolizumab works in treating patients with bladder cancer that has spread into the deep muscle of the bladder wall (muscle-invasive) or urothelial cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced). Monoclonal antibodies recognizing and blocking checkpoint molecules can enhance the patient's immune response and therefore help fight cancer. Pembrolizumab is one of the monoclonal antibodies that block the PD-1 axis and can interfere with the ability of tumor cells to grow.
detailed Description
DUAL PRIMARY OBJECTIVE: I. To determine disease free survival (DFS) and overall survival (OS) in all patients with muscle-invasive bladder and upper-tract urothelial carcinoma treated with adjuvant pembrolizumab versus (vs.) observation. SECONDARY OBJECTIVES: I. To determine DFS and OS in PD-L1 positive and negative patients with muscle-invasive bladder and upper-tract urothelial carcinoma treated with adjuvant pembrolizumab vs. observation. II. To characterize the safety and tolerability of pembrolizumab when administered in the adjuvant setting in patients with muscle-invasive bladder and upper-tract urothelial carcinoma. CORRELATIVE SCIENCE OBJECTIVES: I. To determine if the 12 immune gene signatures are associated with OS and DFS. II. To determine if tumor molecular subtype is associated with OS and DFS. III. To investigate whether the diversity of T-cell receptor (TCR) clonotypes is associated with OS and DFS. IV. To investigate whether persistence of TCR clonotypes is associated with OS and DFS. V. To determine if tumor burden and neoantigen burden are associated with OS and DFS. VI. To determine if HLA subtypes are associated with OS and DFS. VII. To conduct exploratory analyses regarding the association of plasma HGF and VEGF levels with IL-10 and IL-17 and OS and DFS and between treated and untreated patients. PHARMACOGENOMIC STUDY OBJECTIVES: I. To investigate the effect of PDCD1 single-nucleotide polymorphism (SNP) rs11568821 on severe (grade 3 or higher) immune-related toxicity in the pembrolizumab-treated cohort. II. To investigate whether other SNPs commonly polymorphic within or near PDCD1 associate with development of pembrolizumab toxicity in the treated cohort. III. To identify novel germline genetic markers of treatment-related toxicity through genome-wide association analysis of pembrolizumab-treated patients. IV. To identify novel germline genetic markers that are associated with DFS and OS through genome-wide association analysis. QUALITY OF LIFE CORRELATIVE STUDY OBJECTIVES: I. To compare health-related quality of life (HRQL) as assessed by the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-core (C)30 between patients randomized to pembrolizumab vs. observation. II. To compare urinary symptoms as assessed by EORTC QLQ- muscle-invasive bladder cancer module (BLM)30 between patients randomized to pembrolizumab vs. observation. III. To compare patient-reported fatigue, diarrhea, and pain between patients randomized to pembrolizumab vs. observation. IV. To compare health utilities and quality-adjusted life year (QALYs) between patients randomized to pembrolizumab vs. observation. V. To compare other scale scores of the EORTC QLQ-C30, EORTC QLQ-BLM30, and European Quality of Life 5 Dimensions 5 Levels (EQ5D-5L) between patients randomized to pembrolizumab vs. observation. VI. To compare global quality of life, symptoms, health utilities, QALYs, and other scale scores of the three questionnaires between patients randomized to pembrolizumab vs. observation within subgroups defined by each of the stratification factors. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a computed tomography (CT) scan, CT urography, and/or magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo a cystoscopy and blood sample collection during screening and on study. ARM B: Patients undergo observation. Patients undergo a CT scan, CT urography, and/or MRI throughout the trial. Patients may also undergo a cystoscopy and blood sample collection during screening and on study. After completion of study treatment, patients are followed up every 12 weeks for up 2 years, and then annually for 10 years.
Source references
references
  1. citation
    Apolo AB, Ballman KV, Sonpavde G, Berg S, Kim WY, Parikh R, Teo MY, Sweis RF, Geynisman DM, Grivas P, Chatta G, Reichert ZR, Kim JW, Bilen MA, McGregor B, Singh P, Tripathi A, Cole S, Simon N, Niglio S, Ley L, Cordes L, Srinivas S, Huang J, Odegaard M, Watt C, Petrylak D, Hoffman-Censits J, Wen Y, Hahn O, Mitchell C, Tan A, Streicher H, Sharon E, Moon H, Woods M, Halabi S, Perez Burbano G, Morris MJ, Rosenberg JE. Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2025 Jan 2;392(1):45-55. doi: 10.1056/NEJMoa2401726. Epub 2024 Sep 15.
    pmid
    39282902
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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        nivolumab arm died of pneumonitis, and one patient died of a bowel perforation.</li></ul></div></li><li>A randomized controlled trial (<a href="/clinicaltrials/NCT03244384">AMBASSADOR</a> [NCT03244384]) compared adjuvant pembrolizumab with observation in 702 patients. Patients had undergone radical cystectomy and had positive mar
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        itis, and one patient died of a bowel perforation.</li></ul></div></li><li>A randomized controlled trial (<a href="/clinicaltrials/NCT03244384">AMBASSADOR</a> [NCT03244384]) compared adjuvant pembrolizumab with observation in 702 patients. Patients had undergone radical cystectomy and had positive margins, node-positive disease,
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      Bladder Cancer Treatment (PDQ®)–Health Professional Version
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      1. context
        Updated: May 2, 2025
        datetime
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        May 2, 2025

    Preserved source evidence · Not medical advice