A phase 2 study of the Aurora A kinase (AAK) tyrosine kinase inhibitor (TKI) alisertib (MLN8237) in patients (pts) with pretreated urothelial cancer (UC).

Authors

Andrea Necchi

Andrea Necchi

Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

Andrea Necchi , Daniele Raggi , Salvatore Lo Vullo , Luigi Mariani , Patrizia Giannatempo , Giuseppina Calareso , Elena Togliardi , Nicola Nicolai , Federica Perrone , Giuseppe Pelosi , Roberto Salvioni , Filippo G. De Braud

Organizations

Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, National Cancer Institute of Milan, Milan, Italy, Laboratory of Experimental Molecular Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Research Funding

Other

Background: Progress in developing effective salvage therapies for UC is warranted. AAK overexpression has been described in UC and spindle checkpoint (SC) dysregulation is a common feature. Alisertib is an orally available, selective TKI of AAK. Methods: A single-group, Ph2 trial was conducted with Alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT01653028). The primary endpoint was RECIST 1.1 objective response-rate (ORR), and ≥ 3/20 responses were required (H0 ≤ 5%, H1 ≥ 20%, α = 5%/β = 20%) to move to a randomized trial of paclitaxel plus either Alisertib or placebo. Eligibility included failure of ≤ 2 platinum-based regimens. Cox regression analyses were done. Targeted sequencing of pts is being performed through the Ion AmpliSeq Comprehensive Cancer Panel (Life Technologies). Results: From 10/2014 to 04/2015, 22 pts were enrolled (20 evaluable for response), 8 (36.4%) in 2nd line and 14 (63.6%) > 2ndline. 8 (36.4%) had an ECOG-PS 1-2, 3 (13.6%) had Hb < 10mg/dl, 9 (40.9%) had liver metastases. 2 PR (ORR: 10%), 7 stable disease (SD) and 11 PD were recorded. Median FUP was 6.3 mos (IQR: 4.5-8.0). 6m-PFS was 18.2% (95%CI: 7.5-44.1), including 2 pts with 9.7 and 9.5 mos FUP (still ongoing, both > 2nd line). Median PFS was 1.8 mos (IQR: 1.3-3.4), but median OS was not reached (6m-OS: 63.6%, 95%CI: 46.4-87.3). Hb < 10gr/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). AAK-IHC expression did not correlate with outcome. Tissue of pt with 9.7 month SD harbored a missense mutation of mTOR (E1813D*) and the nonsense mutation Q527STOP* of TSC1, together with HER3 and TAF1Lmissense mutations. Grade 3-4 adverse events (AE) were: 54.5% alopecia, 41% mucositis, 36.4% fatigue, 18% neutropenia (14% febrile neutropenia). There were 2 treatment-related deaths (septic shock). Conclusions: Preliminary data suggest the possibility for sustained disease control in about 20% of pts, including very long term PR/SD. Hb ≥ 10 and mutations of TSC1/mTOR (TAF1L?) might be the clinical and biological markers for patient enrichment design with SC inhibitors like Alisertib, although the incidence of AE is a major concern. Clinical trial information: NCT01653028

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Abstract Details

Meeting

2016 Genitourinary Cancers Symposium

Session Type

Poster Session

Session Title

Poster Session B: Prostate Cancer; Urothelial Carcinoma; Penile, Urethral, and Testicular Cancers

Track

Urothelial Carcinoma,Prostate Cancer,Penile, Urethral, and Testicular Cancers

Sub Track

Urothelial Carcinoma

Clinical Trial Registration Number

NCT01653028

Citation

J Clin Oncol 34, 2016 (suppl 2S; abstr 382)

DOI

10.1200/jco.2016.34.2_suppl.382

Abstract #

382

Poster Bd #

F17

Abstract Disclosures