Alisertib in Chemotherapy-pretreated Urothelial Cancer

Study Overview
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Brief Summary
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Background: Progress in developing new effective therapies in advanced and relapsing urothelial cancer has been stagnant in the last few decades and a paradigm shift is desperately needed. Aurora kinase-A overexpression has been previously described in bladder cancer and spindle checkpoint dysregulation is a common feature of human urothelial carcinoma (UC). Alisertib (Millennium Inc.) is an orally available, selective small molecule inhibitor of Aurora A kinase. Single agent and combination treatment of MLN8237 with either paclitaxel (TXL) or gemcitabine synergistically reduced UC cell viability compared with either drug alone. Hence, sequential application of MLN8237 and TXL warrants clinical investigation. Phase 1 trials of both single agent and the combination with TXL defined the recommended doses for phase 2 trials. Methods: A multistep approach will be adopted for this Phase 2 trial. A single-group run-in phase will be conducted first with Alisertib 50 mg orally BID for 7 days, followed by 14d rest until disease progression. In case of activity, a confirmatory randomized (1:1) trial of weekly TXL plus either Alisertib or Placebo will follow, incorporating efficacy and futility boundaries for early stopping. In a single-blind design, TXL will be given on days 1,8,15 q4wks at the dose of 60 mg/m2 with alisertib and 80 mg/m2 with placebo. Alisertib dose will be 40 mg BID days 1-3, 8-10 and 15-17, q4wks. In the single-arm phase, primary endpoint (EP) will be Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response-rate. 20 pts will be accrued, ≥3 responses will be required (10% type I and 20% type II error constraints). An accrual of 110 pts is foreseen in the randomized phase. Primary EP: progression-free survival (PFS), assuming an improvement in PFS from a median of 2.5 months (H0) to a median of 4.5 months (H1) (44% hazard rate reduction, 10% drop out rate). Eligibility will include diagnosis of metastatic UC and failure of 1-2 CT regimens (single-arm) or 1 prior CT only (randomized phase). A relapse within 6 months of a peri-operative CT will be counted as 1 line. Computed tomography and PET will be done every 2 cycles (2 months). Additional pharmacodynamic and translational analyses are planned on pre- post- blood and tissue samples.

Detailed Description
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Phase 2 trial. A single-group run-in phase will be conducted first with Alisertib 50 mg orally BID for 7 days, followed by 14d rest until disease progression.

Official Title
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A Phase 2 Study of the Aurora Kinase A Inhibitor Alisertib (MLN8237) in Patients With Relapsed or Refractory Transitional-cell Carcinoma of the Bladder and Urothelial Tract

Conditions
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Bladder Cancer, Transitional Cell Carcinoma

Intervention / Treatment
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* Drug: Alisertib
* Drug: Paclitaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of transitional cell tumors of the bladder or the urothelium. Locally advanced (T3b,N0; every T,N+) or metastatic disease. Failure of max.2 chemotherapy regimens for metastatic disease (at least 1 including a platinum compound). Neoadjuvant/adjuvant therapy considered if relapse occurred within 6 months of the last cycle of chemotherapy. Exclusion Criteria: Failure to meet the eligibility requirements. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. Major co-morbidities as specified in the protocol.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alisertib + Paclitaxel<br>After the first single arm phase with Alisertib monotherapy (20 patients, primary endpoint: response-rate), 110 patients will be randomized 1:1 in the second part of the trial. | Drug: Alisertib<br>* SINGLE-ARM, SINGLE-DRUG PHASE: Alisertib will be given PO in a dosage of 50 mg BID for 7 Days (Days 1-7) of each 21 day treatment cycle. In the randomized phase, Experimental arm will consist of the following drugs: Alisertib will be given PO in a dosage of 40 mg twice daily on days 1-3, 8-10 and 15-17 of a 28 day cycle. Paclitaxel: 60 mg/m2 over 60 minutes on Days 1, 8, and 15 in a 28-day cycle.<br>* Other names: MLN8237;Drug: Paclitaxel<br>* Placebo will be given PO. Paclitaxel will be infused at the dose of 80 mg/m2 IV over a period of 60 minutes on Days 1, 8, and 15 in a 28-day cycle.<br>* Other names: Taxol;|
| Placebo Comparator: Paclitaxel + Placebo<br>Weekly paclitaxel + oral Placebo | Drug: Paclitaxel<br>* Placebo will be given PO. Paclitaxel will be infused at the dose of 80 mg/m2 IV over a period of 60 minutes on Days 1, 8, and 15 in a 28-day cycle.<br>* Other names: Taxol;Drug: Placebo<br>* Placebo oral tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Single-arm pilot phase: In this phase we will accrue 20 patients, that will be assessed for overall response to treatment (as per RECIST v1.1) as the primary study end point. | 2 months | 
| Progression-free survival | Randomized Phase: Progression free survival will be the primary endpoint. It is foreseen in this phase an accrual of 110 patients, equally balanced in the two arms, in about 36 months and an overall study duration of 40 months, over which we expect to observe 101 disease progressions or deaths. This is the number of events necessary to yield 90% power of a one sided logrank test at the 5% significance level in case of an improvement in PFS from a median of 2.5 months (H0) to a median of 4.5 months (H1), corresponding to a 44% hazard rate reduction in the experimental arm compared to control. | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and tolerability of Alisertib in a population of chemotherapy pretreated patients with UC. | Incidence and nature of adverse events graded according to the Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.03. | 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bladder cancer, Urothelial cancer, Alisertib, Phase 2, Advanced disease