Gemcitabine and Split-Dose Cisplatin Plus Everolimus (RAD001) in Patients With Advanced Solid Tumor Malignancies

Inclusion Criteria:

- Patients must have advanced urothelial cancer histologically confirmed by MSKCC
pathology review.

- Patients may not have received prior systemic chemotherapy for metastatic disease.

- Patients may have received prior neoadjuvant or adjuvant systemic chemotherapy
provided it was completed ≥ 1 year prior to the diagnosis of metastatic disease.

Age ≥ 18 years.

- Karnofsky Performance Status ≥ 70.

- Expected survival of at least 3 months.

- Resolution of all acute toxic effects of prior chemotherapy, radiotherapy, or
surgical procedure to NCI CTCAE grade ≤ 1.

- Adequate bone marrow function as shown by:

- ANC ≥ 1.5x 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 (or < 3 on anticoagulants)

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

Adequate renal function as shown by:

- Serum creatinine ≤ 2.0 mg/dL OR

Calculated creatinine clearance ≥ 50 mL/min/1.73 m2 using the Jelliffe equation:

Calculated creatinine clearance = 98 - 0.8 [age(yrs) - 20] x (0.9 if female) Serum
creatinine (mg/dL)

- 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.

- 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, tyrosine kinase inhibitors, 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 serum pregnancy test within 14 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 6 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.

- Patients with a history of noncompliance to medical regimens.

- Patients unwilling to or unable to comply with the protocol.