PRIMARY OBJECTIVE:
I. To characterize the safety profile of pembrolizumab in patients with urothelial carcinoma
undergoing radical cystectomy.
SECONDARY OBJECTIVES:
I. To explore a signal of anti-cancer immunological activity by evaluating surgical specimens
for evidence of post-treatment lymphocytic infiltration and residual tumor compared to
pre-treatment biopsy samples.
II. To explore a signal of biomarker activity by evaluating surgical specimens and blood
samples for established and not-so-established markers of response to pembrolizumab.
III. To report the tumor yield and sufficiency of tumor for immunological and biomarker
activity.
IV. To examine the interaction of the human microbiome and pathologic response to
pembrolizumab.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 3 weeks for up to 2 cycles in the absence of disease progression or unacceptable
toxicity. About 4 weeks after treatment, patients then undergo radical cystectomy per
standard of care.
After completion of study treatment, patients are followed up to 30 and 90 days.
Inclusion Criteria:
- Be willing and able to provide written informed consent.
- Have absence of metastatic disease as determined by conventional imaging studies and
be considered a good surgical candidate by the treating physician.
- Be willing to participate in the collection of blood and tissue for banking and future
correlative studies.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale.
- Absolute neutrophil count (ANC) >= 1,500 /mcL.
- Platelets >= 100,000/mcL.
- Hemoglobin (Hgb) >= 9 g/dL or >= 5.6 mmol/L without (w/o) transfusion within 7 days of
assessment.
- Creatinine OR calculated creatinine clearance =< 1.5 x upper limit of normal (ULN) OR
>= 30 mL/min for subject with creatinine levels > 1.5 x institutional ULN. Creatinine
clearance should be calculated per institutional standard.
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 x ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN OR =< 5 x ULN for subjects with liver metastases.
- Albumin > 2.5 mg/dL.
- Coagulation international normalized ratio (INR) or prothrombin time (PT) 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.
- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
- Female subjects of childbearing potential must be willing to use an adequate method of
contraception for the course of the study through 120 days after the last dose of
study medication. Note: Abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the subject.
- Male subjects of childbearing potential must agree to use an adequate method of
contraception, starting with the first dose of study therapy through 120 days after
the last dose of study therapy. Note: Abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the subject.
Exclusion Criteria:
- Is currently participating and receiving pembrolizumab or has participated in a study
of an investigational agent and received pembrolizumab or used an investigational
device within 4 weeks of the first dose of study treatment.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of study
treatment.
- Has a known history of active TB (Bacillus tuberculosis).
- Has a known history of hypersensitivity to pembrolizumab or any of its excipients.
- Has had prior systemic anti-cancer therapy for the treatment of bladder cancer. Prior
intravesical therapies, whether Bacillus Calmette-Guerin (BCG) (including but not
limited to: persistent high-grade disease or recurrence within 6 months of receiving
at least two courses of intravesical BCG [at least five of six induction doses and at
least two of three maintenance doses]; or T1 high-grade disease at the first
evaluation following induction BCG alone [at least five of six induction doses]),
chemotherapy or otherwise, will remain eligible.
- Has any other malignancy diagnosed within 2 years of screening with the exception of
basal or squamous cell skin cancer, or non-invasive cancer of the cervix, or any other
cancer deemed by the treating physician to be of low-risk for progression or patient
morbidity during the study period.
- Has known metastatic disease as determined by conventional staging studies.
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
- Has known history of, or any evidence of active, non-infectious pneumonitis.
- Has a clinically significant active infection requiring systemic therapy.
- 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 physician.
- 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.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
- Has 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).
- Has received a live vaccine within 30 days of initiation of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
attenuated vaccines, and are not allowed.
