Phase 2 Study of Pembrolizumab in Combination With Gemcitabine and Cisplatin as Neoadjuvant Therapy

Primary Objective To estimate the proportion of patients with pathological downstaging to
cisplatin in patients with MIBC

Hypothesis: The rate of pathologic downstaging to controls

Secondary Objectives To estimate the proportion of patients with pT0 after neoadjuvant
therapy with pembrolizumab when administered in combination 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 EFS, and OS

To explore associations between BASE47 "basal," "claudin-low," and "luminal" subtypes of MIBC
and pathological downstaging to
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
First the participant will receive all 3 study drugs (Pembrolizumab/Keytruda, gemcitabine and
cisplatin) on the first day of a 3 week "cycle". The partcipant will then receive cisplatin
and gemcitabine 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 calculated 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 (Creatinine
clearance should be calculated per CKD-EPI equation.) 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

- 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