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

  • PHASE II STUDIES
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Summary

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.

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Authors and Affiliations

  1. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy

    Andrea Necchi, Daniele Raggi, Patrizia Giannatempo, Giuseppe Procopio & Filippo G. De Braud

  2. Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

    Salvatore Lo Vullo & Luigi Mariani

  3. Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

    Giuseppina Calareso

  4. Pharmacy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

    Elena Togliardi

  5. Nuclear Medicine and PET Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

    Flavio Crippa

  6. Clinical Trials Center, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

    Nicola Di Genova

  7. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

    Federica Perrone, Maurizio Colecchia, Biagio Paolini & Giuseppe Pelosi

  8. Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

    Nicola Nicolai & Roberto Salvioni

  9. Università degli Studi di Milano, Milano, Italy

    Giuseppe Pelosi & Filippo G. De Braud

Authors
  1. Andrea Necchi
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  2. Salvatore Lo Vullo
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  3. Luigi Mariani
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  4. Daniele Raggi
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  15. Giuseppe Procopio
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Corresponding author

Correspondence to Andrea Necchi.

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Conflict of interest

The authors declare that they have no conflict of interest.

Funding

The study was partially supported by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Next generation sequencing analyses were supported in part by funds obtained through an Italian law that allows taxpayers to allocate 0.5 % share of their income tax contribution to a research Institution of their choice.

Electronic supplementary material

Supplementary Figure 1

Design of the study. Abbreviations: BID: bis-in-die (twice daily); PFS: progression-free survival. (JPEG 509 kb)

Supplementary Table 1

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Supplementary Table 2

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Necchi, A., Lo Vullo, S., Mariani, L. et al. An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer. Invest New Drugs 34, 236–242 (2016). https://doi.org/10.1007/s10637-016-0328-9

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  • DOI: https://doi.org/10.1007/s10637-016-0328-9

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