Background Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A. Methods A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5 %, H1 ≥ 20 %, α = 10 % and β = 20 %). Eligibility included failure of at least one platinum-based regimen. Results From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4 %) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4 %) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1 %), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6 % (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1 %, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9 % mucositis, 36.4 % fatigue, 18.2 % neutropenia (13.6 % febrile neutropenia). There were 2 treatment-related deaths. Conclusions The study did not meet the primary EP, yet sustained disease control was obtained in about 14 % of patients. The incidence of AE and the issue of patient selection are two major concerns.
An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer / A. Necchi, S. Lo Vullo, L. Mariani, D. Raggi, P. Giannatempo, G. Calareso, E. Togliardi, F. Crippa, N. Di Genova, F. Perrone, M. Colecchia, B. Paolini, G. Pelosi, N. Nicolai, G. Procopio, R. Salvioni, F.G. De Braud. - In: INVESTIGATIONAL NEW DRUGS. - ISSN 0167-6997. - 34:2(2016 Apr), pp. 236-242.
|Titolo:||An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer|
NECCHI, ANDREA (Corresponding)
DE BRAUD, FILIPPO GUGLIELMO MARIA (Ultimo)
|Parole Chiave:||alisertib; aurora A kinase; bladder cancer; salvage therapy; urothelial carcinoma; pharmacology; pharmacology (medical); oncology|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||apr-2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1007/s10637-016-0328-9|
|Appare nelle tipologie:||01 - Articolo su periodico|