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