Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer

Patients will be randomized to Arm A: gemcitabine plus carboplatin plus nivolumab versus Arm
B: gemcitabine plus oxaliplatin plus nivolumab. Randomization will be stratified on the
metastasis status (lymph node only vs. the rest). Patients on both treatment arms will
receive up to 6 cycles of combination therapy in the absence of prohibitive adverse effects
or disease progression. Patients with at least stable disease at the completion of 6 cycles
of treatment may continue "maintenance" single agent nivolumab for up to 24 cycles. Patients
who require discontinuation of chemotherapy (i.e., gemcitabine plus carboplatin or
gemcitabine plus oxaliplatin) prior to Cycle 6, but who have at least stable disease, may be
considered for ongoing treatment with single-agent nivolumab on the "maintenance" phase after
discussion with the sponsor-investigator.

Inclusion Criteria:

Subject must meet all the following applicable inclusion criteria to participate in this
study:

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

- Age ≥ 18 years at the time of consent.

- Eastern Cooperative Oncology Group (ECOG) performance status of = 2

- Able to comply with the study protocol, in the investigator's judgment.

- Histologically documented, locally advanced (T4b, any N; or any T, N 2−3) or
metastatic urothelial carcinoma (mUC) (M1, Stage IV) (also termed TCC or UCC of the
urinary tract; including renal pelvis, ureters, urinary bladder, and urethra) Patients
with mixed histologies are required to have a dominant transitional cell pattern.
Locally advanced bladder cancer must be inoperable on the basis of involvement of
pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis
(N2−N3).

- Measurable disease, as defined by RECIST v1.1

- Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (metastatic
specimens preferable but if not available primary tumor specimens that are at least
muscle-invasive are acceptable) in paraffin blocks (blocks preferred) or at least 15
unstained slides. Subjects without adequate archival tumor tissue or for whom a biopsy
is not considered possible may be considered for enrollment on a case by case basis
after discussion with the sponsor-investigator.

- No prior chemotherapy for inoperable locally advanced or mUC. For patients who
received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial
carcinoma, a treatment-free interval > 12 months between the last treatment
administration and the date of recurrence is required in order to be considered
treatment naive in the metastatic setting.

- Cisplatin-ineligible as defined by at least one of the following:

- Calculated creatinine clearance ≥ 30 (Cockroft-Gault)

- ECOG performance status of 2 or greater

- CTCAE v4 Grade ≥ 2 audiometric hearing loss

- Demonstrate adequate organ function. All screening labs to be obtained within 28 days
prior to registration:

- Hematological:

- Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L

- Hemoglobin (Hgb) ≥ 9 g/dL

- Platelets ≥ 100 x 10^9/L

- Renal:

• Calculated creatinine clearance ≥ 30 mL/min (Cockroft-Gault)

- Hepatic:

- Bilirubin ≤ 1.5 × upper limit of normal (ULN) (except subjects with Gilbert
Syndrome, who can have total bilirubin < 3.0 mg/dL)

- Aspartate aminotransferase (AST) ≤ 3 × ULN

- Alanine aminotransferase (ALT) ≤ 3 × ULN

- Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception.

- Women of childbearing potential must have a negative serum or urine pregnancy.

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

- Active infection requiring systemic therapy.

- Pregnant or breastfeeding

- Any serious or uncontrolled medical disorder that, in the opinion of the site
investigator, may increase the risk associated with study participation or study drug
administration, impair the ability of the subject to receive protocol therapy, or
interfere with the interpretation of study results.

- Prior malignancy active within the previous 3 years except for locally curable cancers
that have been apparently cured.

- Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll.

- Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease.

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or
any other antibody or drug specifically targeting T-cell co-stimulation or immune
checkpoint pathways.

- Grade ≥ 2 neuropathy (NCI CTCAE version 4).

- Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
ribonucleic acid (RNA) or hepatitis C antibody (HCV antibody) indicating acute or
chronic infection.

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).

- Evidence of interstitial lung disease or active, non-infectious pneumonitis.

- Significant cardiovascular disease, such as New York Heart Association cardiac disease
(Class III or greater), myocardial infarction within 3 months prior to randomization,
unstable arrhythmias, or unstable angina.

- Known left ventricular ejection fraction (LVEF) < 40% Patients with known coronary
artery disease, congestive heart failure not meeting the above criteria, or LVEF
40%−50% must be on a stable medical regimen that is optimized in the opinion of the
treating physician, in consultation with a cardiologist if appropriate.

- Solid organ or tissue transplant including stem cell transplant