Brief Title
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
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Response rate
Secondary Outcome
To evaluate the safety and tolerability of Alisertib in a population of chemotherapy pretreated patients with UC.
Condition
Bladder Cancer
Intervention
Alisertib
Study Arms / Comparison Groups
Alisertib + Paclitaxel
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
22
Start Date
August 28, 2014
Completion Date
October 12, 2016
Primary Completion Date
July 2, 2015
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.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Andrea Necchi, MD, ,
Location Countries
Italy
Location Countries
Italy
Administrative Informations
NCT ID
NCT02109328
Organization ID
UC-Aurora_INT01
Secondary IDs
2014-000557-36
Responsible Party
Principal Investigator
Study Sponsor
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study Sponsor
Andrea Necchi, MD, Principal Investigator, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Verification Date
April 2019