Trial to Evaluate Paclitaxel Plus RAD001 in Urothelial Carcinoma

• Duration of response [ Time Frame: from first determination of response until progression ] [ Designated as safety issue: No ]
• Progression free survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• overall survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• safety profile of combination RAD001 and paclitaxel [ Time Frame: 6 month ] [ Designated as safety issue: Yes ]

This is a single arm open- label phase II- trial evaluating safety and efficacy of paclitaxel and RAD001 in patients with metastatic urothelial bladder cancer who failed prior platin-based systemic therapy.

The screening phase for checking eligibility and evaluation of the patient prior start of study treatment will last up to 21 days.Tumor histology must be predominant urothelial carcinoma and confirmed histological or cytological.Patients who meet the inclusion criteria will be treated with paclitaxel 175 mg/m2 every 3 weeks and RAD001 10 mg once daily. Each cycle will use the combination of paclitaxel 175 mg/m2 3-weekly with RAD001 10 mg daily starting at day 1 of a 21 days treatment cycle. Additional visits after day 1 are performed at day 8 and day 15 of each cycle Assessment of safety and toxicity will be performed at every visit.

Patients will be treated until no signs of clinical or radiological progression are evident and the study treatment is well tolerated for a maximum of 6 cycles.

• Drug: paclitaxel
  Paclitaxel (175 mg/m3)will be administered as a 3 hour continuous IV infusion after standard premedication every 3 weeks
  Other Name: Taxol
• Drug: RAD001
  10 mg RAD001 once daily starting at day 1 of a 21 days treatment cycle
  Other Name: Certican, Everolimus

Inclusion Criteria:

• Patients with histologically proven carcinoma of the urinary tract including urinary bladder, ureter, renal pelvis and lower urinary tract. Urothelial carcinoma should be the predominant histology
• Confirmation of locally relapsed or metastatic disease by imaging. Measurable disease according to RECIST- guidelines with ≥1 measurable lesion has to be evident.
• If bone is the only metastatic site a quantification of the target lesion(s) using MRI is mandatory.
• Failure of prior platin- based chemotherapy
• Patients may have shown progressive disease within the first 3 months of platin-based chemotherapy (primary failure) or progression within 3 months after the end of platin-based chemotherapy (early relapse)-Prior therapy with ≤ 4 chemotherapeutic drugs
• Patients with tumor relapse within 3 months after cystectomy in the neoadjuvant or adjuvant setting are not eligible.
• ECOG performance status 0-2

• Adequate haematological, liver and renal functions.

  • Neutrophil count > 1500/mm3, haemoglobin > 9 g/dl, platelets ≥ 100.000/ mm3
  • Serum bilirubin ≤ 1.5 x ULN, ALT and AST ≤ 2.5x ULN. Patients with known liver metastases who have an AST and ALT ≤ 5x ULN.
  • serum creatinine ≤ 2 x ULN.
• Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to the first dose of study drug. Female subjects of childbearing potential must be using two acceptable methods of contraception, from the time of screening and for the duration of the study, through study completion and for 3 months following study completion
• Age > 18 years.
• Able to communicate well with the investigator, to understand and comply with the requirements of the study. Understand and sign the written informed consent.
• Patients must give written informed consent
• No concurrent treatment with other experimental drugs or anti-cancer drugs
• Another distinguishable malignancy will be permitted

Exclusion Criteria:

• chemotherapy, radiation therapy or any other anticancer therapy within 4 weeks of the first dose of study drug.
• Participation in any clinical investigation within 4 weeks prior to initial dosing.
• known hypersensitivity to RAD001 or other rapamycin analogs and paclitaxel or other taxanes, or to its excipients.
• previously received RAD001, other mTOR inhibitors or taxanes or epothilones
• known metastasis of central nervous system.
• symptomatic pleural effusions or symptomatic ascites.
• wide field radiation therapy to up to ≥ 25% of the bone marrow within 4 weeks prior therapy.
• intravenous radionuclide therapy, e.g. phosphorus (32P), strontium (89SrCl), rhenium (186Re)or samarium (153Sm).
• Patients who have undergone major surgery within 4 weeks prior to starting study drug,open biopsy, or significant traumatic injury, or who have not recovered from the side effects of any of the above.
• Chronic systemic treatment with corticosteroids corresponding to a prednisone equivalent of > 10 mg daily. Patients receiving corticosteroids must be on a stable dose for ≥ 4 weeks prior to the first dose of RAD001. Topical or inhaled corticosteroids are permitted.
• Concomitant medication with strong CYP3A4- inhibitors or CYP3A4- inducers.
• active bleeding diathesis.
• Neuropathy > grade 1.
• any severe and/or uncontrolled medical conditions(unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months, serious uncontrolled cardiac arrhythmia, uncontrolled hyperlipidemia, active or uncontrolled severe infection,cirrhosis,chronic or persistent active hepatitis)
• severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation ≤ 88% at rest on room air
• Uncontrolled diabetes
• Hepatic impairment with a Child-Pugh score >9
• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not willing to use effective birth control methods.
• Significant non- malignant illness within 2 weeks prior to initial dosing.
• History of immunodeficiency diseases, including a positive HIV test result
• History of drug or alcohol abuse, or evidence of such abuse
• Concurrent medication with oral anticoagulants is no contraindication per se but warrants continuous verification of INR
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs, or which may jeopardize the subject
• Patients with a known or suspected history of hepatitis B or hepatitis C infection have to undergo serological screening (see post-text supplement 4)