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

The purpose of this trial is to explore the activity and safety of everolimus +/- paclitaxel as first-line therapy 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.

Eligibility Criteria:
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.