Alisertib in Chemotherapy-pretreated Urothelial Cancer
Bladder Cancer - Transitional Cell Carcinoma
Conditions: official terms
Carcinoma, Transitional Cell - Urinary Bladder Neoplasms
Conditions: Keywords
Bladder cancer, Urothelial cancer, Alisertib, Phase 2, Advanced disease
Study Type
Study Phase
Phase 2
Study Design
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
Name: Alisertib Type: Drug
Name: Paclitaxel Type: Drug
Name: Placebo Type: Drug
Overall Status
Not yet recruiting

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.


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.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: 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.
Fondazione IRCCS Istituto Nazionale dei Tumori
Milano, Mi, Italy
Status: Not yet recruiting
Contact: Andrea Necchi, MD - +39022390 -
Start Date
April 2014
Completion Date
March 2018
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Record processing date processed this data on July 28, 2015 page