Clinical Trials /

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

NCT03244384

Description:

This randomized 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.

Related Conditions:
  • Bladder Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in Treating Patients With Locally Advanced Bladder Cancer
  • Official Title: Phase III Randomized Adjuvant Study of MK-3475 (Pembrolizumab) in Muscle Invasive and Locally Advanced Urothelial Carcinoma (AMBASSADOR) Versus Observation

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01425
  • SECONDARY ID: NCI-2017-01425
  • SECONDARY ID: A031501
  • SECONDARY ID: A031501
  • SECONDARY ID: A031501
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT03244384

Conditions

  • Stage II Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage III Bladder Urothelial Carcinoma AJCC v6 and v7

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab)

Purpose

This randomized phase III trial studies how well pembrolizumab works in treating patients with bladder cancer that has spread from where it started to nearby tissue or lymph nodes. 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

      PRIMARY OBJECTIVES:

      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 (MK-3475) 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 MK-3475 (pembrolizumab)
      vs. observation.

      II. To characterize the safety and tolerability of MK-3475 (pembrolizumab) when administered
      in the adjuvant setting in patients with muscle-invasive bladder and upper-tract urothelial
      carcinoma.

      TERTIARY 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.

      VIII. To investigate the effect of PDCD1 single-nucleotide polymorphism (SNP) rs11568821 on
      severe (grade 3 or higher) immune-related toxicity in the MK-3475 (pembrolizumab)-treated
      cohort.

      IX. To investigate whether other SNPs commonly polymorphic within or near PDCD1 associate
      with development of MK-3475 (pembrolizumab) toxicity in the treated cohort.

      X. To identify novel germline genetic markers of treatment-related toxicity through
      genome-wide association analysis of pembrolizumab-treated patients.

      XI. To identify novel germline genetic markers that are associated with DFS and OS through
      genome-wide association analysis.

      XII. 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 MK-3475 (pembrolizumab) vs. observation.

      XIII. To compare urinary symptoms as assessed by EORTC QLQ- muscle-invasive bladder cancer
      module (BLM)30 between patients randomized to MK-3475 (pembrolizumab) vs. observation.

      XIV. To compare patient-reported fatigue, diarrhea, and pain between patients randomized to
      MK-3475 (pembrolizumab) vs. observation.

      XV. To compare health utilities and quality-adjusted life year (QALYs) between patients
      randomized to MK-3475 (pembrolizumab) vs. observation.

      XVI. 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 MK-3475
      (pembrolizumab) vs. observation.

      XVII. To compare global quality of life, symptoms, health utilities, QALYs, and other scale
      scores of the three questionnaires between patients randomized to MK-3475 (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 courses in the absence of disease progression or
      unacceptable toxicity.

      ARM B: Patients undergo observation.

      After completion of study treatment, patients are followed up every 12 weeks for up 2 years,
      and then annually for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (observation)Active ComparatorPatients undergo observation.
    Treatment (pembrolizumab)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
    • Pembrolizumab

    Eligibility Criteria

            Inclusion Criteria:
    
              -  PRE-REGISTRATION ELIGIBILITY CRITERIA
    
              -  Histologically confirmed muscle-invasive urothelial carcinoma of the bladder or upper
                 tract; variant histology allowed as long as urothelial carcinoma is predominant (>
                 50%); pure small-cell carcinoma is excluded
    
              -  Paraffin tissue samples obtained by transurethral resection of muscle-invasive bladder
                 tumor, upper tract resection, cystectomy/nephrectomy/ureterectomy, or
                 nephroureterectomy must be available; this specimen submission is mandatory prior to
                 registration as results will be used for stratification
    
              -  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+
    
              -  Patient must have had radical surgical resection of their bladder cancer >= 4 weeks
                 but =< 16 weeks prior to pre-registration
    
              -  No invasive cancer at the surgical margins
    
              -  No evidence of residual cancer or metastasis after surgery
    
              -  No 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) (+) patients are eligible as long as they have: cd4
                 > 200, undetectable viral load and on highly active antiretroviral therapy (HAART)
                 therapy
    
              -  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 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 pregnant and not nursing
    
              -  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
    
              -  Creatinine =< 2.0 x upper limit of normal (ULN) OR calculated (calc.) creatinine
                 clearance >= 30 mL/min
    
              -  Total bilirubin =< 1.5 x upper limit of normal (ULN)
    
              -  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; 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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Overall survival
    Time Frame:From randomization to the date of death from any cause, assessed up to 5 years
    Safety Issue:
    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.

    Secondary Outcome Measures

    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
    Safety Issue:
    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
    Safety Issue:
    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.

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

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