Phase III Randomized Adjuvant Study of MK-3475 (Pembrolizumab) in Muscle Invasive and Locally Advanced Urothelial Carcinoma (Ambassador) versus Observation

Primary objective:
To determine DFS and OS in all patients with muscle-invasive bladder and upper-tract urothelial carcinoma treated with adjuvant MK-3475 (pembrolizumab) vs. observation.

Secondary objectives:

1. 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.
    
2. 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.

Other objective(s):
Results of the primary analysis will be examined for consistency, while taking into account the stratification factors and/or covariates of baseline QOL and fatigue.

Inclusion Criteria:

1. 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
2. Paraffin tissue samples obtained by transurethral resection of muscle-invasive bladder tumor, upper tract resection, or other surgery 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
3. Patient must fit into one of the following three categories:
   • a) Patients who received neoadjuvant chemotherapy and pathologic stage at surgical resection is >= pT2 and/or N+ OR
   • b) 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
   • c) 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+
4. The 7th edition of American Joint Committee on Cancer 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
5. 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
6. 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
7. 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)
8. 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
9. No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years
10. Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible