A Single Arm, Multi-center Phase II Trial to Evaluate Paclitaxel Plus RAD001 in Urothelial Carcinoma After Failure of Prior Platin-based Chemotherapy
- 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
- 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
- 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
- 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)