Study of BEZ235 as Monotherapy in Patients With Transitional Cell Carcinoma After Failure of Platinum Based Chemotherapy

Study Overview
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Brief Summary
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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.

Official Title
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A Single Arm, Multicenter, Phase II Study of BEZ235 as Monotherapy in Patients With Locally Advanced or Metastatic Transitional Cell Carcinoma (TCC) After Failure of Platinum Based Chemotherapy.

Conditions
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Carcinoma Transitional Cell

Intervention / Treatment
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* Drug: BEZ235


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically- or cytologically-confirmed locally advanced or metastatic TCC not amenable to curative surgery or radiation. Documented disease progression (according RECIST 1.1 criteria) after first line platinum-based therapy (given in neoadjuvant/adjuvant or palliative setting). An interval of >4 weeks since last anticancer treatment. 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. At least one measurable lesion by MRI or CT-scan ECOG performance status 0-1, in stable medical condition 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%. Patients must be over 18 years old and able to give written informed consent. Signed informed consent prior to beginning protocol specific procedure Exclusion Criteria: Non- TCC bladder cancer More than 2 prior chemotherapy regimens given for palliation. 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) Patient with active uncontrolled or symptomatic central nervous system (CNS metastases). 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. Other uncontrolled medical condition (active infections requiring antibiotics, bleeding disorders, uncontrolled diabetes …) Other concomitant anticancer therapy. Previous therapy with PI3K and/or mTOR inhibitors (sirolimus, temsirolimus, everolimus) 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 Pregnancy or risk of pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BEZ235, powder<br>Group 1: patients without PI3K pathway activation; no loss of PTEN and no activating PIK3CA mutation. Group 2: patients with PI3K pathway activation as defined by PIK3CA mutation and/or PTEN loss | Drug: BEZ235<br>* The investigational study drug used in this trial is BEZ235, supplied as 200 mg, 300 mg and 400 mg sachets. BEZ235 is administered continuously twice-daily; complete cycle is 28 days. Starting dose is 300mg PO bid. At cycle 1 day 15, based on a clinical assessment, dose is adjusted for the rest of the study:• If no adverse event (AE) or only mild AE (G1) : the dose will be increase to 400 mg bid• If AE = G2 : the patient will continue at 300 mg bid • If G3 AE or higher : BEZ235 will be interrupt until resolved to ≤ G1 then reduce dose to 200 mg bid<br>* Other names: BEZ235 is a potent dual pan class I PI3K and mTOR inhibitor.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the efficacy of BEZ235 in patients with palliative TCC | o Control disease rate at 16 weeks, including complete responses, partial responses and stable diseases according to RECIST criteria. | at 16 weeks (radiological evaluation every 8 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the safety profile of BEZ235 in patients with advanced TCC | The patient will have an appointment with the investigator on day 15 of cycle 1 and every day 1 of each cycle. | participants will be followed for the duration of hospital stay, an expected average of 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TCC, Failure of platinum based chemotherapy