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Trial record 1 of 1 for:    03244384
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Testing MK-3475 (Pembrolizumab) After Surgery for Localized Muscle-Invasive Bladder Cancer and Locally Advanced Urothelial Cancer (AMBASSADOR)

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ClinicalTrials.gov Identifier: NCT03244384
Recruitment Status : Recruiting
First Posted : August 9, 2017
Last Update Posted : February 18, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Localized Renal Pelvis and Ureter Urothelial Carcinoma Locally Advanced Bladder Urothelial Carcinoma Locally Advanced Renal Pelvis and Ureter Urothelial Carcinoma Locally Advanced Ureter Urothelial Carcinoma Locally Advanced Urothelial Carcinoma Stage II Bladder Urothelial Carcinoma AJCC v6 and v7 Stage II Renal Pelvis and Ureter Cancer AJCC v7 Stage II Ureter Cancer AJCC v7 Stage III Bladder Urothelial Carcinoma AJCC v6 and v7 Stage III Renal Pelvis and Ureter Cancer AJCC v7 Stage III Ureter Cancer AJCC v7 Other: Clinical Observation Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Other: Pharmacological Study Other: Quality-of-Life Assessment Other: Questionnaire Administration Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 739 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Randomized Adjuvant Study of MK-3475 (Pembrolizumab) in Muscle Invasive and Locally Advanced Urothelial Carcinoma (AMBASSADOR) Versus Observation
Actual Study Start Date : September 21, 2017
Estimated Primary Completion Date : June 1, 2025
Estimated Study Completion Date : June 1, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A (pembrolizumab)
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.
 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
Active Comparator: Arm B (observation)
Patients undergo observation.
 Other: Clinical Observation
Undergo observation
Other Name: observation

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 transuretheral 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+
  • 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
  • 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
  • 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] 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

Exclusion Criteria:

  • 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
  • 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) (+) 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
  • 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 currently requiring hemodialysis
  • 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03244384


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Andrea B Apolo Alliance for Clinical Trials in Oncology
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03244384    
Other Study ID Numbers: 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 )
First Posted: August 9, 2017    Key Record Dates
Last Update Posted: February 18, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Ureteral Neoplasms
Kidney Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
 Urogenital Neoplasms
Neoplasms by Site
Ureteral Diseases
Urologic Diseases
Kidney Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents