Alisertib in Chemotherapy-pretreated Urothelial Cancer

NCT ID: NCT02109328

Last Updated: 2019-04-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-08-28
• Study Completion Date: 2016-10-12

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.

Conditions

Bladder Cancer; Transitional Cell Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Alisertib

Intervention Type: DRUG

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.

Paclitaxel

Intervention Type: DRUG

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.

Paclitaxel + Placebo

Weekly paclitaxel + oral Placebo

Group Type: PLACEBO_COMPARATOR

Paclitaxel

Intervention Type: DRUG

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.

Placebo

Intervention Type: DRUG

Placebo oral tablets

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Placebo

Placebo oral tablets

Intervention Type: DRUG

Other Intervention Names

MLN8237; Taxol

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

OTHER

Sponsor Role: lead

Responsible Party

Andrea Necchi

Dr.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrea Necchi, MD

Role: PRINCIPAL_INVESTIGATOR

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Locations

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Mi, Italy

Countries

Italy

References

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.

Reference Type: DERIVED

PMID: 28155045 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26873642 (View on PubMed)

Other Identifiers

2014-000557-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

UC-Aurora_INT01

Identifier Type: -

Identifier Source: org_study_id