Alisertib in Chemotherapy-pretreated Urothelial Cancer

April 9, 2019 updated by: Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

22

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • Mi
      • Milano, Mi, Italy, 20133
        • Fondazione IRCCS Istituto Nazionale dei Tumori

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Alisertib + Paclitaxel
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

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.

Other Names:
  • MLN8237
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.
Other Names:
  • Taxol
Placebo Comparator: Paclitaxel + Placebo
Weekly paclitaxel + oral Placebo
Drug: Placebo
Placebo oral tablets
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.
Other Names:
  • Taxol

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response rate
Time Frame: 2 months

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
Time Frame: 2 months

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.
Time Frame: 2 months
Incidence and nature of adverse events graded according to the Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.03.
2 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Translational outcomes
Time Frame: 2 months
Correlation with tissue and circulating biomarkers with the clinical outcome.
2 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Investigators

  • Principal Investigator: Andrea Necchi, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 28, 2014

Primary Completion (Actual)

July 2, 2015

Study Completion (Actual)

October 12, 2016

Study Registration Dates

First Submitted

April 3, 2014

First Submitted That Met QC Criteria

April 7, 2014

First Posted (Estimate)

April 9, 2014

Study Record Updates

Last Update Posted (Actual)

April 11, 2019

Last Update Submitted That Met QC Criteria

April 9, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UC-Aurora_INT01
  • 2014-000557-36 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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