Alisertib in Chemotherapy-pretreated Urothelial Cancer

NCT02109328 | Completed Phase 2

• 2 other identifiers: UC-Aurora_INT012014-000557-36
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Bladder Cancer; Transitional Cell Carcinoma

Keywords

Bladder cancer; Urothelial cancer; Alisertib; Phase 2; Advanced disease

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  2 months

Secondary Outcomes (1)

• To evaluate the safety and tolerability of Alisertib in a population of chemotherapy pretreated patients with UC.

  2 months

Other Outcomes (1)

• Translational outcomes

  2 months

Study Arms (2)

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.

Drug: Alisertib; Drug: Paclitaxel

Paclitaxel + Placebo

PLACEBO COMPARATOR

Weekly paclitaxel + oral Placebo

Drug: Paclitaxel; Drug: Placebo

Interventions

Alisertib 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.

Also known as: MLN8237

Alisertib + Paclitaxel

Paclitaxel 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.

Also known as: Taxol

Alisertib + Paclitaxel; Paclitaxel + Placebo

Placebo DRUG

Placebo oral tablets

Paclitaxel + Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Mi, 20133, Italy

Location

Related Publications (2)

• 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.

  PMID: 28155045 DERIVED

• 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.

  PMID: 26873642 DERIVED

MeSH Terms

Conditions

Urinary Bladder Neoplasms; Carcinoma, Transitional Cell

Interventions

MLN 8237; Paclitaxel

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Andrea Necchi, MD

  Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr.

Study Record Dates

• First Submitted: April 3, 2014
• First Posted: April 9, 2014
• Study Start: August 28, 2014
• Primary Completion: July 2, 2015
• Study Completion: October 12, 2016
• Last Updated: April 11, 2019

Record last verified: 2019-04

Locations

IT (1)