Clinical trial NCT02109328: Alisertib in Chemotherapy-pretreated Urothelial Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bladder Cancer
Transitional Cell Carcinoma
Keywords: Bladder cancer
Urothelial cancer
Alisertib
Phase 2
Advanced disease
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
First posted: 2014-04-09
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility 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.

Primary outcomes:
measure: Response rate
timeFrame: 2 months
measure: Progression-free survival
timeFrame: 2 months
Secondary outcomes:
measure: To evaluate the safety and tolerability of Alisertib in a population of chemotherapy pretreated patients with UC.
timeFrame: 2 months
Other outcomes:
measure: Translational outcomes
timeFrame: 2 months
Locations:
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: Mi
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
name: Andrea Necchi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Necchi A, Pintarelli G, Raggi D, Giannatempo P, Colombo F. Association of an aurora kinase a (AURKA) gene polymorphism with progression-free survival in patients with advanced urothelial carcinoma treated with the selective aurora kinase a inhibitor alisertib. Invest New Drugs. 2017 Aug;35(4):524-528. doi: 10.1007/s10637-017-0440-5. Epub 2017 Feb 3.
citation: Necchi A, Lo Vullo S, Mariani L, Raggi D, Giannatempo P, Calareso G, Togliardi E, Crippa F, Di Genova N, Perrone F, Colecchia M, Paolini B, Pelosi G, Nicolai N, Procopio G, Salvioni R, De Braud FG. An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer. Invest New Drugs. 2016 Apr;34(2):236-42. doi: 10.1007/s10637-016-0328-9. Epub 2016 Feb 12.