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

Not Recruiting

Trial ID: NCT03244384


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.

Official Title

Phase III Randomized Adjuvant Study of Pembrolizumab in muScle invaSive and locAlly aDvanced urOthelial caRcinoma (AMBASSADOR) Versus Observation

Stanford Investigator(s)

Sandy Srinivas
Sandy Srinivas

Professor of Medicine (Oncology) and, by courtesy, of Urology


Inclusion 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

   - 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

   - 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


other: Clinical Observation

biological: Pembrolizumab

other: Pharmacological Study

other: Quality-of-Life Assessment

other: Questionnaire Administration

procedure: Biospecimen Collection

procedure: Computed Tomography

procedure: CT Urography

procedure: Cystoscopy

procedure: Magnetic Resonance Imaging

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Sneha Mohile

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