Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Alisertib in Chemotherapy-pretreated Urothelial Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02109328
Recruitment Status : Completed
First Posted : April 9, 2014
Last Update Posted : April 11, 2019
Sponsor:
Information provided by (Responsible Party):
Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

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.


Condition or disease Intervention/treatment Phase
Bladder Cancer Transitional Cell Carcinoma Drug: Alisertib Drug: Paclitaxel Drug: Placebo Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
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
Actual Study Start Date : August 28, 2014
Actual Primary Completion Date : July 2, 2015
Actual Study Completion Date : October 12, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer
Drug Information available for: Paclitaxel

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 Name: 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 Name: Taxol

Placebo Comparator: Paclitaxel + Placebo
Weekly paclitaxel + oral Placebo
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 Name: Taxol

Drug: Placebo
Placebo oral tablets




Primary Outcome Measures :
  1. 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. 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.



Secondary Outcome Measures :
  1. 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.


Other Outcome Measures:
  1. Translational outcomes [ Time Frame: 2 months ]
    Correlation with tissue and circulating biomarkers with the clinical outcome.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02109328


Locations
Layout table for location information
Italy
Fondazione IRCCS Istituto Nazionale dei Tumori
Milano, Mi, Italy, 20133
Sponsors and Collaborators
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Investigators
Layout table for investigator information
Principal Investigator: Andrea Necchi, MD Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Andrea Necchi, Dr., Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
ClinicalTrials.gov Identifier: NCT02109328     History of Changes
Other Study ID Numbers: UC-Aurora_INT01
2014-000557-36 ( EudraCT Number )
First Posted: April 9, 2014    Key Record Dates
Last Update Posted: April 11, 2019
Last Verified: April 2019

Keywords provided by Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:
Bladder cancer
Urothelial cancer
Alisertib
Phase 2
Advanced disease

Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action