First-line Everolimus +/- Paclitaxel for Cisplatin-ineligible Patients With Advanced Urothelial Carcinoma

OUTLINE: This is a multi-center study

Patients will be enrolled into one of two parallel cohorts:

- Cohort 1: impaired renal function AND poor performance status (cycle length = 28 days).
Everolimus 10 mg orally daily

- Cohort 2: impaired renal function OR poor performance status (cycle length = 28 days).
Everolimus 10 mg orally daily + IV Paclitaxel 80 mg/m2 on D1, 8, 15

Restaging evaluations will be performed after every 2 cycles.

Treatment will continue until disease progression or unacceptable toxicity.

Karnofsky performance status 60-70%

Life Expectancy: Not specified

Hematopoietic:

- Absolute neutrophil count (ANC) ≥ 1.5 K/mm3

- Hemoglobin (Hgb) ≥ 9 g/dL

- Platelets ≥ 100 K/mm3

- INR ≤ 1.5 (Anticoagulants are allowed if target INR ≤ 1.5 on a stable dose of warfarin
or on a stable dose of Low molecular weight (LMW) heparin for at least 2 weeks prior to
registration for protocol therapy).

- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L

- Fasting triglycerides ≤ 2.5 x ULN.

- Fasting serum glucose < 1.5 x ULN

Hepatic:

- Bilirubin ≤ 1.5 x ULN

- Aminotransferases (AST and ALT) ≤ 2.5 x ULN (unless liver metastases, then ≤ 5 x ULN)

Renal:

- Calculated creatinine clearance of < 60 using the Cockcroft-Gault formula

Cardiovascular:

- No symptomatic congestive heart failure of New York heart Association Class III or IV.

- No 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.

Inclusion Criteria:

- Histological or cytological proof of transitional cell carcinoma (TCC) of the bladder,
urethra, ureter, or renal pelvis (urothelial carcinoma). Histology may be mixed, but
still requires a component of TCC.

- Measurable disease according to RECIST and obtained by imaging within 30 days prior to
registration for protocol therapy.

- Must be ineligible for cisplatin, based on the following, within 30 days prior to
registration for protocol therapy.

- Prior radiation therapy is allowed to < 25% of the bone marrow.

- Written informed consent and HIPAA authorization for release of personal health
information.

- Age > 18 years at the time of consent.

- Females of childbearing potential and males must be willing to use an effective method
of contraception (hormonal or barrier method of birth control; abstinence) from the
time consent is signed until 8 weeks after treatment discontinuation.

- Females of childbearing potential must have a negative pregnancy test within 7 days
prior to prior to registration for protocol therapy.

- Females must not be breastfeeding.

Exclusion Criteria:

- No prior chemotherapy for metastatic disease. Prior chemotherapy in the
neoadjuvant/adjuvant setting is allowed if completed at least 12 months prior to
registration for protocol therapy.

- No active CNS metastases or leptomeningeal metastases. Patients with neurological
symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis.

- No prior malignancy is allowed except for adequately treated basal cell or adequately
treated squamous cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate
cancers (treated definitively with no evidence of PSA progression), or other cancer
for which the patient has been disease-free for at least 5 years.

- No treatment with any anticancer therapy or investigational agent within 30 days prior
to registration for protocol therapy.

- No known hypersensitivity to any protocol treatment.

- No prior treatment with mTOR inhibitor (sirolimus, temsirolimus, everolimus).

- No history of immunization with attenuated live vaccines within one week prior to
registration for protocol therapy or during study period.

- No severely impaired lung function as defined as spirometry and DLCO that is 50% of
the normal predicted value and/or 02 saturation that is 88% or less at rest on room
air.

- No uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.

- No active (acute or chronic) or uncontrolled severe infections.

- No liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis.

- No known history of HIV seropositivity.

- No 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).

- No active, bleeding diathesis.

- No history of major surgery (defined as requiring general anesthesia) or significant
traumatic injury within 30 days prior to registration for protocol therapy.