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Pembrolizumab in Treating Patients With Locally Advanced Bladder Cancer (AMBASSADOR)

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ClinicalTrials.gov Identifier: NCT03244384
Recruitment Status : Recruiting
First Posted : August 9, 2017
Last Update Posted : May 23, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE August 7, 2017
First Posted Date  ICMJE August 9, 2017
Last Update Posted Date May 23, 2019
Actual Study Start Date  ICMJE September 21, 2017
Estimated Primary Completion Date June 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 2, 2018)
  • Overall survival [ Time Frame: From randomization to the date of death from any cause, assessed up to 5 years ]
    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.
  • 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 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 8, 2017)
  • 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 ]
    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.
  • Overall survival [ Time Frame: From randomization to the date of death from any cause, assessed up to 5 years ]
    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.
Change History Complete list of historical versions of study NCT03244384 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2018)
  • 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 ]
    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.
  • 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 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 8, 2017)
  • 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 ]
    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.
  • 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 ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pembrolizumab in Treating Patients With Locally Advanced Bladder Cancer
Official Title  ICMJE Phase III Randomized Adjuvant Study of MK-3475 (Pembrolizumab) in Muscle Invasive and Locally Advanced Urothelial Carcinoma (AMBASSADOR) Versus Observation
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Stage II Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage III Bladder Urothelial Carcinoma AJCC v6 and v7
Intervention  ICMJE
  • Other: Clinical Observation
    Undergo observation
    Other Name: observation
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Pembrolizumab
    Given IV
    Other Names:
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • SCH 900475
  • Other: Pharmacological Study
    Correlative studies
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
Study Arms  ICMJE
  • Active Comparator: Treatment (observation)
    Patients undergo observation.
    Interventions:
    • Other: Clinical Observation
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
  • Experimental: Treatment (pembrolizumab)
    Patients 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.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Biological: Pembrolizumab
    • Other: Pharmacological Study
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 8, 2017)
739
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2025
Estimated Primary Completion Date June 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03244384
Other Study ID Numbers  ICMJE NCI-2017-01425
NCI-2017-01425 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A031501
A031501 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A031501 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Andrea B Apolo Alliance for Clinical Trials in Oncology
PRS Account National Cancer Institute (NCI)
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP