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)