Pembrolizumab and Docetaxel or Gemcitabine Hydrochloride in Treating Patients Urothelial Cancer

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of MK-3475 (pembrolizumab) when given in
combination with docetaxel or gemcitabine (gemcitabine hydrochloride) in patients with
advanced or metastatic platinum-treated urothelial cancer.

SECONDARY OBJECTIVES:

I. To assess in a preliminary manner the efficacy of this combination (overall response rate
and progression free survival).

II. To determine in an exploratory manner programmed death (PD)-ligand (L)1 expression in
archival tumor specimens and to correlate this with patient outcomes.

OUTLINE: This is a dose-escalation study of pembrolizumab. Patients are assigned to 1 of 2
treatment arms. (Patients who had received prior gemcitabine hydrochloride/cisplatin or
gemcitabine hydrochloride/carboplatin [GC] or methotrexate, vinblastine sulfate, adriamycin,
and cisplatin [MVAC] therapy are assigned to Arm A).

ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and
docetaxel IV over 60 minutes on day 1.

ARM B: Patients receive pembrolizumab IV as in Arm A and gemcitabine hydrochloride IV over 30
minutes on days 1 and 8.

In both arms, treatment repeats every 21 days for 12 months in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 6 months.

Inclusion Criteria:

- Have locally advanced or metastatic urothelial cancer that is not amenable to curative
surgical treatment

- Have histologically or cytologically confirmed urothelial tract carcinoma

- Be previously chemotherapy-treated; all patients may have received up to two prior
lines of chemotherapy (excludes systemic therapy) for recurrent/advanced disease, as
long as one of those regimens was platinum-based; (it is anticipated that patients
would have been previously treated with MVAC or GC, or variations of these standard
frontline regimens)

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

- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1

- Have provided tissue from an archival tissue sample or newly obtained core or
excisional biopsy of a tumor lesion

- Life expectancy of greater than 6 months

- Have a performance status of 0 to 1 on the Zubrod performance scale

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

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated*
creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X
institutional ULN; (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl])

- Creatinine clearance should be calculated per institutional standard

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 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

- Alkaline phosphatase not applicable (N/A)

- International normalized ratio (INR) or prothrombin time (PT) =<1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (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 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 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

- 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

Exclusion Criteria:

- 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 treatment

- Has known hypersensitivity to MK-3475 (pembrolizumab) or any of its incipients

- Patients with a known hypersensitivity to gemcitabine (Arm B only)

- Patients with hypersensitivity to docetaxel or polysorbate 80 (Arm A only)

- 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

- 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: Subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

- 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; free
of disease for more than 5 years

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment

- Has an 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; anti-coagulants are permitted

- Has evidence of interstitial lung disease or active, non-infectious pneumonitis

- Has an active serious bacterial infection requiring systemic antimicrobial 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-cluster of
differentiation (CD)137, 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., 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 prior to the first dose of trial treatment