Phase II Study of 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 < 1.3 (or < 3 on anticoagulants)

- ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)

- Adequate renal function: serum creatinine ≤ 1.5 x ULN

- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5
x ULN. NOTE: If a patient's lipid values exceed either one of these criteria upon
screening, the patient can only become eligible after successful initiation of
appropriate lipid-lowering medication. After lipid-lowering therapy, patients must
meet the same criteria - i.e. a fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L
AND fasting triglycerides ≤ 2.5 x ULN - to be eligible for study treatment

- Signed informed consent.

- Testing for hepatitis B viral load and serological markers (HBV-DNA, HBsAg, HBsAb,
and HBcAb) for the following patients:

- All patients who currently live in (or have lived in) Asia, Africa, Central and
South America, Eastern Europe, Spain, Portugal, or Greece

- Patients with any of the following risk factors:

- Known or suspected past hepatitis B infection Blood transfusion(s) prior to 1990

- Current or prior IV drug users

- Current or prior dialysis

- Household contact with hepatitis B infected person(s)

- Current or prior high-risk sexual activity

- Body piercing or tattoos

- Mother known to have hepatitis B History suggestive of hepatitis B infection, e.g
dark urine, jaundice, or right upper quadrant pain

- Additional patients at the discretion of the investigator

- Testing for hepatitis C infection (using quantitative RNA-PCR) for patients with any
of the following risk factors:

- Known or suspected past hepatitis C infection (including patients with past
interferon "curative" treatment)

- Blood transfusion(s) prior to 1990

- Current or prior IV drug users

- Household contact of hepatitis C infected person(s)

- Current or prior high-risk sexual activity

- Body piercing or tattoos

- Additional patients at the discretion of the investigator

Exclusion Criteria:

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of study drug (including chemotherapy,
radiation therapy, antibody based therapy, etc.)

- Patients who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia), or patients who may require
major surgery during the course of the study.

- Prior treatment with any investigational drug within the preceding 4 weeks.

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent, except corticosteroids with a daily dosage equivalent to
prednisone ≤ 20 mg. Patients receiving these corticosteroids must have been on a
stable dosage regimen for a minimum of 4 weeks prior to the first treatment with
Everolimus. Topical or inhaled corticosteroids are allowed.

- Patients should not receive immunization with attenuated live vaccines within one
week of study entry or during study period.

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases.

- Evidence of another active cancer, except for non-melanoma skin carcinoma, in-situ
carcinoma of the cervix curatively treated, and adenocarcinoma of the prostate that
has been surgically treated with a post-treatment PSA that is non-detectable

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York Heart Association Class III or IV.

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia, or
any other clinically significant cardiac disease.

- Severely impaired lung function as evidenced by:

(TLC) <50% predicted, OR (FVC) <50% predicted OR, (DLCO) <40% predicted

- Uncontrolled diabetes as defined by fasting serum glucose >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.