Everolimus (RAD001) in Metastatic Transitional Cell Carcinoma of the Urothelium

Inclusion Criteria

• Patients must have a diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis, with histological confirmation at MSKCC.
• Patients must have progressive metastatic disease. Progressive disease will be defined as new or progressive lesions on cross-sectional imaging.
• Patients must have at least one measurable site of disease (according to RECIST criteria) that has not been previously irradiated.
• Patients must have been previously treated, as defined by the following:

Treatment with at least one prior cytotoxic agent but not more than four prior cytotoxic agents. Up to four prior chemotherapy agents are allowed, since conventional chemotherapy ranges from just one drug (e.g., gemcitabine) to regimens that contain four agents (e.g., M-VAC is a four-drug regimen containing methotrexate, vinblastine, doxorubicin, and cisplatin).

• The prior therapy must have included at least one of the following: cisplatin, carboplatin, paclitaxel, docetaxel, or gemcitabine.
• The prior cytotoxic agents may have been administered in the perioperative or metastatic setting and may have been administered sequentially (e.g., first-line treatment followed by second-line treatment at time of progression) or as part of a single regimen.
• Patients must have pre-treatment tumor tissue available for analysis of m-TOR pathway markers. One paraffin block or 10 freshly-prepared unstained slides (on positively charged slides for immunohistochemistry) from the most representative single paraffin-embedded tumor tissue block. Slides from the primary tumor are preferred. If both the primary and metastatic tumor blocks are available, 10 slides from each of the sites should be submitted. If tissue from the primary tumor is not available, a paraffin block or unstained slides from a metastatic site are acceptable. Fine needle aspirates (FNAs) have insufficient tumor tissue and are not permitted.
• Age ≥ 18 years
• Karnofsky Performance Status ≥ 60%
• Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >9 g/dL
• Adequate liver function as shown by:
• serum bilirubin ≤ 1.5 x ULN
• INR 1.5 x ULN.
• Active (acute or chronic) or uncontrolled severe infections.
• Liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis.
• A known history of HIV seropositivity.
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Everolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Patients with an active, bleeding diathesis.
• Female patients who are pregnant or breast-feeding, Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of Everolimus.
• Adults of reproductive potential who are not using effective birth control methods. Men and women of childbearing potential must be willing to use effective barrier method contraception during the trial and for at least three months thereafter. Patients are encouraged to continue barrier -method contraception for two years or longer after treatment. Hormonal contraceptives are not acceptable as a sole method of contraception
• Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).
• Patients with a known hypersensitivity to Everolimus (RAD001) or other rapamycins (sirolimus, temsirolimus) or to its excipients.
• History of noncompliance to medical regimens.
• Patients unwilling to or unable to comply with the protocol.