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