First-Line Gemcitabine, Cisplatin + Ipilimumab for Metastatic Urothelial Carcinoma

OUTLINE: This is a multi-center study

Gemcitabine 1000 mg/m2 Days 1 & 8 Cisplatin 70 mg/m2 Day 1 Ipilimumab 10 mg/kg Day 1 (start
cycle 3)

Treatment during the induction phase will be administered in six 21-day cycles. During cycles
1 and 2, gemcitabine plus cisplatin will be administered WITHOUT ipilimumab. During cycles
3-6, combination therapy with gemcitabine, cisplatin, plus ipilimumab will be administered.
Patients without evidence of disease progression (by irRC) after completion cycle 6 will
continue single-agent ipilimumab maintenance every 3 months.

Karnofsky performance status (KPS) ≥ 80% within 14 days prior to registration for protocol
therapy.

Life Expectancy: Not Specified

Hematopoietic:

- White blood cell count (WBC) ≥ 3.5K/mm3

- Hemoglobin (Hgb) ≥ 9 g/dL

- Platelets ≥ 100K/mm3

- Absolute neutrophil count (ANC) ≥ 1.5k/mm3

Hepatic:

- Bilirubin ≤ 1.5 times x Upper Limit of Normal (ULN) (except patients with Gilbert's
Syndrome, who must have a total bilirubin less than 3.0 mg/dL)

- Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN. NOTE: If the patient has liver
metastases present, then ≤ 5 x ULN

Renal:

- Calculated creatinine clearance of ≥ 55 cc/min using the Cockcroft-Gault formula

Cardiovascular: Not Specified

Inclusion Criteria:

- Histological or cytological proof of urothelial carcinoma of the urethra, bladder,
ureters, or renal pelvis.

- Advanced (clinical stage T4b, unresectable) or metastatic disease.

- Prior radiation therapy is allowed to < 25% of the bone marrow.

- Age > 18 years at the time of consent.

- Written informed consent and HIPAA authorization for release of personal health
information.

- Females must not be pregnant or breastfeeding.

- WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L
or equivalent units of HCG) within 72 hours before the start of ipilimumab.

- Men of fathering potential must be using an adequate method of contraception to avoid
conception throughout the study [and for up to 26 weeks after the last dose of
investigational product] in such a manner that the risk of pregnancy is minimized.

- Prior Autoimmune disease: Patients with a history of inflammatory bowel disease,
including ulcerative colitis and Crohn's Disease, are excluded from this study, as are
patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic
progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune
vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune
origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Patients with other
immune disorders should not be enrolled without discussion with the principal
investigator.

Exclusion Criteria:

- No active CNS metastases. Subjects with neurological symptoms must undergo a head CT
scan or brain MRI to exclude brain metastasis.

- No prior malignancy is allowed except for cancers that have been definitively treated
with a risk of recurrence of < 30% based on the treating oncologists assessment.

- Patients may not have received prior systemic chemotherapy for metastatic/advanced
urothelial carcinoma. Prior neoadjuvant/adjuvant therapy is permitted if completed ≥
12 months prior to registration for protocol therapy. Prior intravesical therapy is
permitted.

- No treatment with any investigational agent within 30 days prior to registration for
protocol therapy.

- No underlying medical or psychiatric condition, which in the opinion of the
investigator will make the administration of ipilimumab hazardous or obscure the
interpretation of AEs, such as a condition associated with frequent diarrhea.

- No non-oncology vaccine therapy used for prevention of infectious diseases (for up to
1 month before or after any dose of ipilimumab).

- No history of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4
inhibitor or agonist.

- No known active or chronic infection with HIV, Hepatitis B, or Hepatitis C.

- No clinically significant infections as judged by the treating investigator.

- No chronic systemic corticosteroids (defined as the equivalent of prednisone ≥ 20 mg
PO daily for > 6 months during the past year)