DUAL PRIMARY OBJECTIVE:
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 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 pembrolizumab vs.
observation.
II. To characterize the safety and tolerability of pembrolizumab when administered in the
adjuvant setting in patients with muscle-invasive bladder and upper-tract urothelial
carcinoma.
CORRELATIVE SCIENCE 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.
PHARMACOGENOMIC STUDY OBJECTIVES:
I. To investigate the effect of PDCD1 single-nucleotide polymorphism (SNP) rs11568821 on
severe (grade 3 or higher) immune-related toxicity in the pembrolizumab-treated cohort.
II. To investigate whether other SNPs commonly polymorphic within or near PDCD1 associate
with development of pembrolizumab toxicity in the treated cohort.
III. To identify novel germline genetic markers of treatment-related toxicity through
genome-wide association analysis of pembrolizumab-treated patients.
IV. To identify novel germline genetic markers that are associated with DFS and OS through
genome-wide association analysis.
QUALITY OF LIFE CORRELATIVE STUDY OBJECTIVES:
I. 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 pembrolizumab vs. observation.
II. To compare urinary symptoms as assessed by EORTC QLQ- muscle-invasive bladder cancer
module (BLM)30 between patients randomized to pembrolizumab vs. observation.
III. To compare patient-reported fatigue, diarrhea, and pain between patients randomized to
pembrolizumab vs. observation.
IV. To compare health utilities and quality-adjusted life year (QALYs) between patients
randomized to pembrolizumab vs. observation.
V. 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 pembrolizumab vs.
observation.
VI. To compare global quality of life, symptoms, health utilities, QALYs, and other scale
scores of the three questionnaires between patients randomized to 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 cycles 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.
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+
- 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
detected)
- 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
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
- 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
