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
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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