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

• Progression-Free Survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  To determine the progression-free survival (using irRC) of patients with advanced/metastatic urothelial carcinoma treated with gemcitabine, cisplatin, and ipilimumab.
• Best Overall Response Rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  To determine the best overall response rate to treatment with gemcitabine, cisplatin, plus ipilimumab
• Number of Adverse Events Experienced by Patients [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  To determine the safety of treatment with gemcitabine, cisplatin, plus ipilimumab.

Gemcitabine plus cisplatin is standard treatment for advanced urothelial cancer. Ipilimumab has shown intriguing activity as neoadjuvant therapy in patients with clinically localized bladder cancer undergoing radical cystectomy. The combination of gemcitabine, cisplatin, plus ipilimumab may build on the chemosensitivity of urothelial carcinoma to produce more durable responses and improved outcomes.

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

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

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)