first-line everolimus +/- paclitaxel for cisplatin-ineligible patients with advanced urothelial carcinoma

Conditions: Transitional Cell Carcinoma; Bladder Carcinoma; Urothelial Carcinoma

Summary: 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.