Neoadjuvant Pembrolizumab in Combination With Gemcitabine Therapy in Cis-eligible/Ineligible UC Subjects

OUTLINE: This is a multi-center study.

INVESTIGATIONAL TREATMENT:

Phase Ib Dose-Finding Cohort I Cisplatin-Eligible:

Phase Ib is a 3+3 design for the cisplatin-eligible group only. Cisplatin-eligible subjects
receive: gemcitabine 1000mg/m2 IV D1 and D8 every 21 days repeated for 4 cycles; cisplatin
70mg/m2 IV D1 and D8 every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min
must follow split dosing of cisplatin over two days). Pembrolizumab will be given every 3
weeks for 5 doses, with a starting dose of 200 mg. NOTE: the last dose of pembrolizumab falls
on what would be D8 of a 5th 'chemo' cycle, however gemcitabine/cisplatin is NOT GIVEN.

Phase II Arm A: Cohort I Cisplatin-Eligible:

Cisplatin-eligible subjects receive: gemcitabine 1000mg/m2 IV D1 and D8 every 21 days
repeated for 4 cycles; cisplatin 70mg/m2 IV D1 and D8 every 21 days, repeated for 4 cycles.
(Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days).
Pembrolizumab at recommended phase II dose (RP2D) is given every 3 weeks for 5 doses starting
with C1D8. NOTE: the last dose of pembrolizumab falls on what would be day 8 of a 5th 'chemo'
cycle, however gemcitabine/cisplatin is NOT GIVEN. Cohort I treatment with gemcitabine and
cisplatin will continue for a maximum of 4 cycles (cycle = 21days).

Phase II Arm B: Cohort II:

Cisplatin-ineligible subjects receive gemcitabine 1000mg/m2 IV D1, D8 and D15 every 28 days,
repeated for 3 cycles. Pembrolizumab at RP2D is given every 3 weeks for 5 doses starting with
C1D8. NOTE: due to the timing of gemcitabine cycles every 4 weeks, and every three week
dosing of pembrolizumab, there are two doses of pembrolizumab given during cycle 2: D1 and
D22. Additionally, the last dose of pembrolizumab falls on what would be D8 of a 4th 'chemo'
cycle; however gemcitabine is NOT GIVEN. Cohort II treatment with gemcitabine will continue
for a maximum of 3 cycles (cycle = 28 days)

Subjects will then have surgery to remove their primary tumor within 2-7 weeks after their
last dose of neoadjuvant therapy.

Eastern Cooperative Oncology Group (ECOC) performance status: 0-1 for cisplatin-eligible
subjects; 0-2 for cisplatin-ineligible subjects.

Demonstrate adequate organ function as defined by the following laboratory values at study
entry. All screening labs should be performed within 28 days of C1D1.

Hematopoetic:

- Absolute neutrophil count (ANC) ≥1,500 /mcL

- Absolute lymphocyte count ≥350 mcL

- Platelets ≥100,000 / mcL

- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

Renal:

- Measured or calculated creatinine clearance ≥30 mL/min

Hepatic:

- Serum total bilirubin ≤ 1.25 X ULN OR ≤ 2.5 x ULN for subjects with Gilbert's disease

- Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤ 2 X
ULN

Coagulation:

- 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

- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
anticoagulant therapy and as long as PT or PTT is within therapeutic range of intended
use of anticoagulants

Inclusion Criteria:

- Be willing and able to provide written informed consent for the trial.

- Over 18 years of age on day of signing informed consent.

- Have histologically confirmed muscle invasive disease of the urinary bladder, renal
pelvis, or ureters.

- Histology must be urothelial carcinoma (transitional cell carcinoma) or urothelial
carcinoma with mixed histology/features.

- Clinical stage cT2-4aN0M0. Please see exclusion criteria for acceptable N0
determination/lymph node size.

- Have a surgical evaluation that documents the plan for multimodality therapy with a
consolidative radical cystectomy or nephroureterectomy.

NOTE on surgical intent: Criteria for acceptable surgical risk are not defined and per
treating urologist. Minimum guidance on surgical intent includes subjects who do not have
significant cardiovascular disease such as NHYA class III or IV heart failure, unstable
arrhythmias or angina, active CAD, and/or EF<25%. Specific diagnostic testing to determine
surgical intent is not required and per treating urologist or oncologist discretion.

- Have an archived tumor block available to submit unstained slides for PD-L1
expression, basal and luminal subtype analysis; MANDATORY. If slides are not
available, a biopsy is strongly encouraged to obtain tissue for submission

- Subjects on full dose anticoagulants must be on a stable regimen of warfarin or low
molecular weight heparin (LMWH) for at least two weeks.

- Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to study registration. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test is required.

- Female subjects of childbearing potential must be willing to use 2 methods of birth
control, be surgically sterile, or abstain from heterosexual intercourse for the
course of the study and through 120 days after the last dose of study medication.
NOTE: Subjects of childbearing potential are those who have not been surgically
sterilized or have not been free from menses for > 1 year.

- Male subjects must agree to use a barrier method of male contraception starting with
the first dose of study therapy and through 120 days after the last dose of study
therapy.

COHORT I - CISPLATIN-ELIGIBLE:

In addition to the inclusion criteria listed above, Cohort I subjects must satisfy all of
the following criteria:

- Glomerular filtration rate (GFR) or creatinine clearance (Ccr) ≥ 50 mL/min. (24 hour
urine preferred). The cisplatin dose will be split over two days for values between
50-59 mL/min

- ECOG PS 0, 1 (and not 2)

- Hearing impaired ≤ grade 1 (may or may not be enrolled in a monitoring program)

- Peripheral neuropathy ≤grade 1

COHORT II - CISPLATIN-INELIGIBLE:

In addition to the inclusion criteria listed above, Cohort II subjects must also meet any
ONE of the following criteria:

- GFR or Ccr: 30-49 (24 hour urine preferred).

- ECOG PS 2

- Hearing impaired ≥grade 2 as assessed by treating physician (may or may not be
enrolled in a monitoring program).

- Peripheral neuropathy of Grade 2-4

Exclusion Criteria:

Subjects may not have any of the following:

- A non-surgical approach recommended by the treating urologist due to any reason.
Criteria for surgical intent are not defined and, rather, suitability is determined
and documented by the subject's treating urologist. Minimum guidance on surgical
intent includes subjects who do not have significant cardiovascular disease such as
NHYA class III or IV heart failure, unstable arrhythmias or angina, active CAD, and/or
EF<25%. Specific cardiopulmonary diagnostic testing to determine surgical intent is
not required and per treating urologist or oncologist discretion.

- Has abdomino-pelvic short axis lymph node of ≥15mm without biopsy. NOTE: A subject
with a staging biopsy proving a non-neoplastic process/N0 will meet inclusion.

- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 28 days prior to study registration.

- Has a diagnosis of immunodeficiency or received systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to study registration. Subjects
on steroids for physiologic replacement due to a non-cancer related cause would not be
excluded.

- Has had a prior monoclonal antibody ≤ 28 days prior to study registration or who has
not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
administered more than 28 days earlier.

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy for
urothelial carcinoma.

- Has a known additional malignancy that is progressing or required treatment ≤ 48
months of study registration. Exceptions include basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, in situ cervical cancer that has undergone
potentially curative therapy, stable (as defined by PSA change, checked within 30
days) and untreated very low-risk or low-risk prostate cancer defined by current NCCN
guidelines.

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Brain imaging is not required and per discretion of treating physician.

- Has an active autoimmune 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. NOTE: Subjects with vitiligo
or resolved childhood asthma/atopy would be an exception. 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
Sjogren's syndrome will not be excluded from the study.

- Has known 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 therapy with hematopoietic growth factor such as G-CSF or GM-CSF in the
14 days prior to registration.

- 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 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 received a live vaccine within 30 days prior to the first dose of trial treatment.
NOTE: Examples of live vaccines include, but are not limited to, the following:
measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral)
vaccines. Seasonal influenza vaccines for injection are generally killed virus
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are
live attenuated vaccines, and are not allowed.