Clinical Trials

Pre-Registration Eligibility Criteria:

Documentation of Disease

• Histologically confirmed muscle-invasive urothelial carcinoma of the bladder, urethra or upper tract or LN+ disease. Variant histology allowed as long as urothelial carcinoma is predominant (any amount of squamous differentiation is allowed).
• Pure small-cell carcinoma is excluded.
• Any component of neuroendocrine carcinoma is excluded.

Tissue available for Central PD-L1 Testing

• Paraffin tissue samples obtained by transurethral resection of muscle-invasive bladder tumor, upper tract resection, radical cystectomy/nephrectomy/ureterectomy/nephroureterectomy, cystoprostatectomy and 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 and LN dissection) are preferred over transuretheral resection, if available.

Disease Status

• 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:
    • 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 [38]) 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+.

Surgical History

• The 7th edition of AJCC staging will be utilized.
• Patient must have had radical cystectomy (either simultaneously or in the past), nephrectomy, nephroureterectomy or ureterectomy ≥ 4 weeks but ≤ 16 weeks prior to pre-registration.  Cystoprostatectomy for men and lymph node dissection (for bladder primary) and (for upper tract tumors) or urethrectomy are allowed.  Patients who have had a partial cystectomy are not eligible.
• No gross cancer at the surgical margins. Microscopic invasive positive margins are allowed. CIS at margins is considered negative margins.
• No evidence of urothelial carcinoma, residual cancer or metastasis after surgery.
• No metastatic disease (or radiologic findings “concerning” for metastatic disease) on cross-sectional imaging (according to RECIST v1.1 criteria).

Patient History

• 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 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. HIV (+) patients are eligible as long as they have: cd4 >200, undetectable viral load and on 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, Sjögren’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., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

Prior Treatment

• 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 preregistration.
• 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 old.
• 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.

Required Pre-Registration Lab Values

• 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 ULN.
• Bilirubin for patients w/Gilbert’s ≤ 3.0 x ULN.
• Calc. Creatinine Clearance > 20 ml/min (using either CKD-EP1 equation or Cockroft-Gault formula).
• AST/ALT ≤ 3.0 x 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.

Patient Registration Eligibility Criteria:

• Central PD-L1 results 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 will 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.