An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer

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.

Investigational new drugs. 2016 Feb 12 [Epub ahead of print]

Andrea Necchi, Salvatore Lo Vullo, Luigi Mariani, Daniele Raggi, Patrizia Giannatempo, Giuseppina Calareso, Elena Togliardi, Flavio Crippa, Nicola Di Genova, Federica Perrone, Maurizio Colecchia, Biagio Paolini, Giuseppe Pelosi, Nicola Nicolai, Giuseppe Procopio, Roberto Salvioni, Filippo G De Braud

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy. Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy. , Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy. , Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Pharmacy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Nuclear Medicine and PET Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Clinical Trials Center, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy. , Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. , Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy.

PubMed