Study of BEZ235 as Monotherapy in Patients With Transitional Cell Carcinoma After Failure of Platinum Based Chemotherapy
Study of BEZ235 as Monotherapy in Patients With Transitional Cell Carcinoma After Failure of Platinum Based Chemotherapy
The mTOR (mammalian Target of Rapamycin) protein is the center of the mTOR pathway that plays
 an important role in cell growth, proliferation, survival and angiogenesis through sensing
 and integrating energetic signals from cellular environment. The mTOR protein is composed of
 two complex, mTOR complex 1 (mTOR C1) and mTOR complex 2 (mTOR C2).

 In regards of mTOR pathway dysregulations observed in TCC development, there is a rational to
 test BEZ23 in advanced TCC. BEZ235 is a pan-class I PI3K inhibitor that, in addition, binds
 to the catalytic site of mTOR, inhibiting mTOR C1 and mTOR C2.
Inclusion Criteria:

 1. Patients with histologically- or cytologically-confirmed locally advanced or
 metastatic TCC not amenable to curative surgery or radiation.

 2. Documented disease progression (according RECIST 1.1 criteria) after first line
 platinum-based therapy (given in neoadjuvant/adjuvant or palliative setting).

 3. An interval of >4 weeks since last anticancer treatment.

 4. Archival paraffin-embedded tumor tissue (block or at least 20 unstained slides) of the
 primary tumor and/or metastases. The most recent archival tissue is mandatory.
 Recidive of the disease should lead to perform if possible novel biopsies, as major
 oncogenic differences are found between primary tumor and secondary lesions.

 5. At least one measurable lesion by MRI or CT-scan

 6. ECOG performance status 0-1, in stable medical condition

 7. Patients must have adequate organ function: Hemoglobin ≥ 9 g/100 ml, neutrophils ≥
 1,000/mm3, platelets ≥ 100,000/mm, INR ≤ 1.5, total serum bilirubin ≤ 1.5 x ULN,
 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or <5.0
 x ULN if hepatic metastases are present), creatinine £1.5 x ULN, fasting plasma
 glucose <140mg/dl, HbA1c < 8%.

 8. Patients must be over 18 years old and able to give written informed consent.

 9. Signed informed consent prior to beginning protocol specific procedure

 Exclusion Criteria:

 1. Non- TCC bladder cancer

 2. More than 2 prior chemotherapy regimens given for palliation.

 3. Concurrent malignancy or previous malignancy in the last 3 years prior to start the
 study treatment (with the exception of a history of adequately treated cervical
 carcinoma in situ or non-melanoma skin cancer)

 4. Patient with active uncontrolled or symptomatic central nervous system (CNS
 metastases).

 5. Significant active cardiac disease including uncontrolled high blood pressure,
 unstable angina, congestive heart failure, myocardial infarction within the previous 6
 months, or serious cardiac arrhythmias.

 6. Other uncontrolled medical condition (active infections requiring antibiotics,
 bleeding disorders, uncontrolled diabetes …)

 7. Other concomitant anticancer therapy.

 8. Previous therapy with PI3K and/or mTOR inhibitors (sirolimus, temsirolimus,
 everolimus)

 9. Concomitant drugs such as coumarin and warfarin, and drugs known to induce torsade de
 pointe, drugs known to be moderate or strong inhibitors or inducers of CYP3A4

 10. Pregnancy or risk of pregnancy.