NCT02109328

Alisertib in Chemotherapy-pretreated Urothelial Cancer

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

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 22 (actual)
• Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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

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.

Conditions

• Bladder Cancer
• Transitional Cell Carcinoma

Interventions

Type	Name	Description
DRUG	Alisertib	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.
DRUG	Paclitaxel	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.
DRUG	Placebo	Placebo oral tablets

Timeline

• Start date: 2014-08-28
• Primary completion: 2015-07-02
• Completion: 2016-10-12
• First posted: 2014-04-09
• Last updated: 2019-04-11

Locations

1 site across 1 country: Italy