Bladder CancerPhase 2NCT02109328
Alisertib in Chemotherapy-pretreated Urothelial Cancer
A Phase 2 study testing Alisertib and Paclitaxel in people with Bladder Cancer and Transitional Cell Carcinoma, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Bladder Cancer, Transitional Cell Carcinoma
- What is being tested?
- Alisertib and Paclitaxel
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- 1 siteItaly
- Study dates
- 28 Aug 2014to 12 Oct 2016
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
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).
Read more
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.
Read the 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.
- Conditions
- Bladder Cancer, Transitional Cell Carcinoma
- Being tested
- Alisertib, Paclitaxel, Placebo
- Keywords
- Bladder cancer, Urothelial cancer, Alisertib, Phase 2, Advanced disease
- Medical subject headings
- Urinary Bladder Neoplasms, Carcinoma, Transitional Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AlisertibDrug
Also called MLN8237
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.
PaclitaxelDrug
Also called Taxol
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.
PlaceboDrug
Placebo oral tablets
| Study group | Role | What they receive |
|---|---|---|
| Alisertib + Paclitaxel | Experimental | 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. Receives: Drug: Alisertib; Drug: Paclitaxel |
| Paclitaxel + Placebo | Placebo comparator | Weekly paclitaxel + oral Placebo Receives: Drug: Paclitaxel; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Response rate
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.
Measured: 2 months
Progression-free survival
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.
Measured: 2 months
Secondary outcomes (1)
To evaluate the safety and tolerability of Alisertib in a population of chemotherapy pretreated patients with UC.
Incidence and nature of adverse events graded according to the Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.03.
Measured: 2 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2014 (estimated)
- Study start28 Aug 2014
- Primary completion2 Jul 2015
- Study completion12 Oct 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Bladder CancerStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Istituto Nazionale dei Tumori, MilanoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
- Investigators
- Andrea Necchi, MD, Principal investigator, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02109328
- Sponsor's protocol ID
- UC-Aurora_INT01
- Other IDs
- 2014-000557-36, 2014
- Status last verified
- Apr 2019
- First submitted
- 3 Apr 2014
- Last updated
- 11 Apr 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 28155045Necchi 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.
PubMed 26873642
Study at a glance
From the registry record, last updated by the sponsor on 11 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02109328
- Acronym / sponsor ID
- UC-Aurora_INT01
- Conditions
- Bladder Cancer, Transitional Cell Carcinoma
- Keywords
- Bladder cancer, Urothelial cancer, Alisertib, Phase 2, Advanced disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Fondazione IRCCS Istituto Nazionale dei Tumori, MilanoUniversity, hospital or other
- Study start
- 28 Aug 2014 (actual)
- Primary completion
- 2 Jul 2015 (actual)
- Study completion
- 12 Oct 2016 (actual)
- First posted
- 9 Apr 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Alisertib + Paclitaxel | Experimental | Drug: Alisertib, Drug: PaclitaxelAfter 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. |
| Paclitaxel + Placebo | Placebo comparator | Drug: Paclitaxel, Drug: PlaceboWeekly paclitaxel + oral Placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AlisertibAlso: MLN8237SINGLE-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. | Drug | Alisertib + Paclitaxel |
| PaclitaxelAlso: TaxolPlacebo 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. | Drug | Alisertib + Paclitaxel, Paclitaxel + Placebo |
| PlaceboPlacebo oral tablets | Drug | Paclitaxel + Placebo |
Primary outcome
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.
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.
1 secondary outcome
To evaluate the safety and tolerability of Alisertib in a population of chemotherapy pretreated patients with UC.
Time frame: 2 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Apr 2019.
- Derived from this study: PubMed 28155045Necchi 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.
- Derived from this study: PubMed 26873642Necchi 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrea Necchi, MD principal investigator
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Alisertib and Paclitaxel in people with Bladder Cancer and Transitional Cell Carcinoma, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Response rate (time frame: 2 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02109328, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Apr 2019.