| Eligibility |
Inclusion Criteria:
1. Be willing and able to provide written informed consent for the trial.
2. Be >/= 18 years of age on day of signing informed consent.
3. Histologically confirmed muscle invasive transitional cell carcinoma of the bladder
(Note: urothelial carcinoma invading into the prostatic stroma with no histologic
muscle invasion is allowed, provided that the extent of disease is confirmed via
imaging and/or EUA. Patients with mixed histologies are required to have a dominant
transitional cell pattern)
4. Clinical stage T2-T4a N0/X M0 disease according to TNM classification (within 4 weeks
before registration)
5. Medically appropriate candidate for radical cystectomy as per urologic oncologist
6. Representative formalin-fixed paraffin embedded (FFPE) bladder tumor samples with an
associated pathology report that are determined to be available and sufficient for
central testing. If an insufficient amount of tumor tissue is available prior to the
start of the screening phase, subjects must consent to allow the acquisition of
additional tumor tissue for performance of central testing.
7. Patients who refuse neoadjuvant cisplatin based chemotherapy or in whom neoadjuvant
cisplatin based therapy is not appropriate for the following conditions:
1. ECOG performance status of 2
2. Creatinine clearance (calculated according to MDRD formula or measured) less than
1mL/s
3. CTCAE version 4.0, grade 2 or above audiometric hearing loss
4. CTCAE version 4.0, grade 2 or above peripheral neuropathy
8. Adequate bone marrow function obtained within 14 days before registration
1. Absolute neutrophil count = 1,500/mm3
2. Hb =9 g/dL or =5.6 mmol/L without transfusion or EPO dependency (within 7 days of
assessment)
3. Platelet count = 100,000/mm3
9. Adequate organ function obtained within 14 days before registration
1. Bilirubin = 1.5 times upper limit of normal (ULN) or Direct bilirubin = ULN for
subjects with total bilirubin levels > 1.5 ULN
2. Alkaline phosphatase = 2 x upper limit of normal (ULN);
3. AST and ALT =2.5 x upper limit of normal (ULN);
4. Creatinine clearance > 30 ml/min according to MDRD formula
5. Albumin >2.5 mg/dL
10. Adequate Coagulation function
1. International Normalized ratio (INR) or Prothrombin Time (PT) =1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants
2. Activated Partial Thromboplastin Time (aPTT) =1.5 X ULN unless subject is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
of intended use of anticoagulants
11. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 14 days prior to the first dose of study treatment. Both sexually active
females and males (and their female partners) patients must agree to use two methods
of highly effective contraception, one of them being a barrier method, or to abstain
from sexual activity during the study and for at least 4 months after last study drug
administration.
12. Patient affiliated to a social security regimen or beneficiary of the same
Exclusion Criteria:
1. Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks before the first dose of study
treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of systemic immunosuppressive therapy within 7 days prior to the first dose
of study treatment (except local/topical or aerosol steroids)
3. Has a known history of active TB (Bacillus Tuberculosis)
4. Hypersensitivity to pembrolizumab or any of its excipients
5. Has had a prior monoclonal antibody within 4 weeks or 5 halflife time (whatever the
shortest) prior to the first dose of study treatment or who has not recovered (i.e., =
Grade 1 or at baseline) from adverse events due to agents administered more than 4
weeks earlier.
6. Has had prior intra-venous chemotherapy, targeted small molecule therapy, or radiation
therapy for bladder cancer
7. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.
8. Has an active autoimmune / immune mediated inflammatory disease requiring systemic
treatment within the past 3 months or a documented history of clinically severe
autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive
agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an
exception to this rule. Subjects that require intermittent use of bronchodilators or
local steroid injections would not be excluded from the study. Subjects with
hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be
excluded from the study.
9. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).
14. Positive for Human Immunodeficiency Virus (HIV) antibody testing
15. Active or chronic hepatitis C and/or B infection. Patients with past/resolved HBV
infection (defined as the presence of antihepatitis B core antibody, IgG anti-HBs +)
are eligible. HBV DNA should be obtained in these patients prior to the first dose of
study treatment. Patients positive for HCV antibody are eligible only if PCR is
negative for HCV RNA
16. Has received a live attenuated vaccine within 30 days prior to the first dose of study
treatment
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