Testing MK-3475 (Pembrolizumab) After Surgery for Localized Muscle-Invasive Bladder Cancer and Locally Advanced Urothelial Cancer
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.
- 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
- Eligible Ages
- Over 18 Years
- Eligible Genders
- Accepts Healthy Volunteers
- 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
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
- No gross cancer at the surgical margins; microscopic invasive urothelial carcinoma
positive margins are allowed; carcinoma in situ (CIS) at margins is considered
- 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
- 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)
- 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
- 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 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
- Not pregnant and not nursing, because this study involves an investigational agent
whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
- 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
- Phase 3
- Study Type
- Intervention Model
- Parallel Assignment
- Primary Purpose
- None (Open Label)
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.||
Arm B (observation)
|Patients undergo observation.||
- National Cancer Institute (NCI)
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 (MK-3475) versus (vs.) observation.
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 MK-3475 (pembrolizumab) vs. observation.
II. 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.
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 MK-3475 (pembrolizumab)-treated cohort.
II. To investigate whether other SNPs commonly polymorphic within or near PDCD1 associate with development of MK-3475 (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 MK-3475 (pembrolizumab) vs. observation.
II. To compare urinary symptoms as assessed by EORTC QLQ- muscle-invasive bladder cancer module (BLM)30 between patients randomized to MK-3475 (pembrolizumab) vs. observation.
III. To compare patient-reported fatigue, diarrhea, and pain between patients randomized to MK-3475 (pembrolizumab) vs. observation.
IV. To compare health utilities and quality-adjusted life year (QALYs) between patients randomized to MK-3475 (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 MK-3475 (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 MK-3475 (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.