Primary Objective To estimate the proportion of patients with pathological downstaging to
<pT2 after neoadjuvant therapy with pembrolizumab when administered prior to and with
gemcitabine and cisplatin in patients with MIBC
Hypothesis: The rate of pathologic downstaging to <pT2 will improve compared to historical
controls
Secondary Objectives To estimate the proportion of patients with pT0 after neoadjuvant
therapy with pembrolizumab when administered prior to and with gemcitabine and cisplatin in
patients with MIBC
Hypothesis: The rate of pathologic downstaging to pT0 will improve compared to historical
controls
To estimate event free survival (EFS) Hypothesis: EFS will be improved compared to
historical controls
To estimate overall survival (OS) Hypothesis: OS will be improved compared to historical
controls
To estimate the proportion of patients who are alive at 3 years (OS at 3 years) Hypothesis:
OS at 3 years will be improved compared to historical controls
To characterize the toxicity profile for the combination of pembrolizumab, gemcitabine, and
cisplatin Hypothesis: Pembrolizumab, gemcitabine, and cisplatin will be a safe combination
with acceptable toxicity rates
Exploratory Objectives To explore the association of biological markers including PD-L1
expression and immune gene expression signatures with pathological downstaging to <pT2, pT0,
EFS, and OS
To explore associations between BASE47 "basal," "claudin-low," and "luminal" subtypes of
MIBC and pathological downstaging to <pT2, pT0, EFS, and OS
To characterize the change in phenotype of TILs, including delineation of effector and
regulatory T cells, before and after neoadjuvant treatment
To define T cell receptor (TCR) and B cell receptor (BCR) repertoire profiles that are
associated with pathological downstaging to <pT2, pT0, EFS, and OS
First the participant will receive a dose of pembrolizumab alone. Two weeks after this dose,
then s/he will receive all 3 study drugs (pembrolizumab, gemcitabine and cisplatin) on the
first day of a 3 week "cycle". S/he will then receive 1 or 2 of these drugs on the 8th day
of the cycle. The participant will receive the study drugs for 4 cycles for a total of 12
weeks.
Participants are followed for 5 years.
Inclusion Criteria:
- Be able to give written IRB approved informed consent and be able to follow protocol
requirements.
- Be greater than or equal to 18 years of age on day of signing informed consent.
- Has a performance status of 0 or 1 on the ECOG Performance Scale
- Has histologically confirmed urothelial carcinoma of the bladder; those with mixed
histology, including a component of urothelial carcinoma, are eligible. Pure small
cell carcinoma, pure adenocarcinoma, and pure squamous cell carcinoma are excluded.
- Has clinical stage T2-T4a N0/X M0 urothelial carcinoma. Clinical T stage is based on
the pre-study standard of care transurethral resection of the bladder tumor (TURBT)
sample and imaging studies.
- Has staging scans with abdominal/pelvic CT or MRI scan and CT scan or x-ray of the
chest within 4 weeks prior to treatment initiation
- Be a medically appropriate candidate for radical cystectomy as determined by an
attending urologist and be planning to receive cystectomy.
- Has had no prior systemic cytotoxic chemotherapy for urothelial carcinoma (prior
intravesicular chemotherapies are permitted)
- Patients must have tumor tissue from transurethral resection of the bladder tumor
(TURBT) available for submission that is sufficient for correlative testing, and
agree to submission of a paraffin block or 20 formalin-fixed paraffin embedded (FFPE)
slides of 5-10 microns in thickness. Patients must also agree to submission of tissue
from cystectomy.
- Demonstrate adequate organ function as defined in the table below; all screening labs
should be performed within 10 days of treatment initiation.
Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL
Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of
assessment) Renal Serum creatinine OR Measured or calculateda creatinine clearance (CrCL;
GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum
total bilirubin ≤ 1.5 X ULN (≤ 3 X ULN if Gilbert's Syndrome) OR Direct bilirubin ≤ ULN
for subjects with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
anticoagulant therapy. If subject receiving anticoagulants, PT or PTT should be within
therapeutic range of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
- Female subjects of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of pembrolizumab.
- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the
course of the study through 120 days after the last dose of study medication Subjects
of childbearing potential are those who have not been surgically sterilized or have
not been free from menses for > 1 year. The two birth control methods can be composed
of: two barrier methods or a barrier method plus a hormonal method to prevent
pregnancy. Subjects should start using birth control from the screening visit and
continue throughout the study period up to 120 days after the last dose of study
therapy.
The following are considered adequate barrier methods of contraception: diaphragm, condom
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal
contraceptives will include any registered and marketed contraceptive agent that contains
an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or
intramuscular agents).
- Male subjects should 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.
- Life expectancy greater than 3 months
- Consents to whole blood collection prior to initiating therapy and at cystectomy for
support of correlative research studies
Exclusion Criteria:
The subject must be excluded from participating in the trial if the subject meets any of
the following:
- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of
pembrolizumab.
- 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
trial treatment. NOTE: see exception to use of systemic steroid as prophylactic
anti-emetic prior to cisplatin in section 4.2.2. Inhaled and topical steroids are
allowed.
- Has a known history of active TB (Bacillus Tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients.
- Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has
not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent.
• Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy.
- 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.
- 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 (eg., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.
- Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
- Has an 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 investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- 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, 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)
- Has received prior radiation therapy to the bladder for the purpose of treating
urothelial carcinoma
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
- Has clinically relevant hearing impairment > Grade 2
- Has received a live vaccine within 30 days prior to the first dose of trial treatment
