Testing the PD-1 Inhibitor Pembrolizumab as Maintenance Therapy After Initial Chemotherapy in Metastatic Bladder Cancer

OUTLINE: This is a multi-center trial.

Eligible subjects will be 1:1 randomized to placebo (Control Arm A) and pembrolizumab
(Experimental Arm B). Stratification factors for randomization: presence of visceral
metastatic disease (lung, liver, or bone or other organs vs. lymph node only) at the time of
initiation of first-line chemotherapy, and response to first-line chemotherapy (CR/PR vs. SD.
Subjects who progress on placebo will be assessed to determine if they are eligible to cross
over to unblinded treatment with pembrolizumab.

INVESTIGATIONAL TREATMENT:

For Control Arm A, commercially available normal saline will be used as the placebo. No
active placebo drug will be mixed with the normal saline.

For Experimental Arm B, pembrolizumab (or placebo), 200 mg intravenous infusion (IV) every 3
weeks for up to 12 months, or until progressive disease (PD) or unacceptable toxicity.

The following required laboratory values must be obtained within fourteen days prior to
registration for protocol therapy:

Hematopoietic:

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

- Platelets ≥100,000 / mcL

- Hemoglobin ≥8.5 g/dL

Renal:

- Creatinine ≤1.5x ULN OR

- Measured or calculated creatinine clearance ≥30 mL/min for subject with creatinine
levels >1.5x institutional ULN

- GFR can also be used in place of creatinine or CrCl

Hepatic:

- Serum total bilirubin ≤ 1.5 X ULN OR

- Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subject with liver metastases

Coagulation:

- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN. If subject is
on anticoagulant therapy, PT or PTT must be within therapeutic range of intended use of
anticoagulants.

Inclusion Criteria:

- Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.

- Age ≥ 18 years at the time of consent.

- ECOG Performance Status (PS) of ≤ 1 within fourteen days of registration for protocol
therapy.

- Histological or cytological evidence of urothelial cancer of the bladder, urethra,
ureter, or renal pelvis. Differentiation with variant histologies (e.g., squamous cell
differentiated) will be permitted provided that the predominant histology is
urothelial carcinoma.

- Metastatic and/or unresectable (cT4b) disease

- Must have achieved an objective response (CR/PR) or stable disease (SD) after 4 to 6
cycles of standard first-line platinum-based chemotherapy for mUC (e.g., as per NCCN
guidelines). Able to commence study treatment within 2 to 6 weeks of receiving last
dose of first-line chemotherapy.

- All subjects must have adequate archival tissue available prior to registration (i.e.,
at least 20 unstained slides or paraffin block). If acceptable archival tissue is not
available, the subject must be willing to consent to providing a core or excisional
biopsy for research prior to registration for protocol therapy. If archival tissue is
not available and there are no sites amenable to biopsy, enrollment must be discussed
with the sponsor-investigator on a case by case basis.

- Female subjects of childbearing potential must have a negative serum pregnancy within
three days prior to registration for protocol therapy

- Sexually active, pre-menopausal women of childbearing potential must be willing to use
an adequate method of contraception or be surgically sterile, or abstain from
heterosexual activity for the course of the study through 120 days after the last dose
of study drug. Subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > one year.

- Male subjects of childbearing potential must agree to use an adequate method of
contraception starting with the first dose of study drug through 120 days after the
last dose of study drug.

Exclusion Criteria:

- More than one line of prior chemotherapy for metastatic or locally advanced disease,
with the following exception:

- Prior neoadjuvant/adjuvant chemotherapy will not count as line of therapy if
completed greater than 12 months prior to initiation of chemotherapy regimen for
metastatic or unresectable disease.

- Current or past participation in a study of an investigational agent or using an
investigational device within four weeks of registration for protocol therapy.

- A diagnosis of immunodeficiency or is receiving treatment with systemic steroid
therapy or any other form of immunosuppressive therapy within seven days prior to
registration for protocol therapy.

- Prior chemotherapy, targeted small molecule therapy, or radiation therapy within two
weeks prior to registration for protocol therapy. Note: If the subjects have undergone
major surgery, they must have recovered adequately from the toxicity and/or
complications from the intervention prior to starting protocol therapy.

- 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.

- A 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 registration for protocol therapy 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 seven days prior to registration for protocol therapy.

- Active autoimmune disease that has required systemic treatment in 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 active, non-infectious pneumonitis.

- Has a history of interstitial lung disease.

- An active infection requiring systemic therapy.

- 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.

- 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 screening period through 120 days
after the last dose of protocol therapy.

- 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).
Examples include nivolumab, MPDL3280, etc.

- A known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- A known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Receipt of a live vaccine within 30 days prior to registration for protocol therapy.

- Unresolved toxicity (i.e., > Grade 1 or above baseline) due to previously administered
agents. Exception includes: subjects with ≤ Grade 2 neuropathy are eligible for the
study.