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Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer

Basu, B, Krebs, M G, Sundar, R, Wilson, R H, Spicer, J, Jones, R, Brada, M, Talbot, D C, Steele, N, Ingles Garces, A H, Brugger, W, Harrington, E A, Evans, J, Hall, E, Tovey, H, de Oliveira, F M, Carreira, S, Swales, K, Ruddle, R, Raynaud, F I, Purchase, B, Dawes, J C, Parmar, M, Turner, A J, Tunariu, N, Banerjee, S, de Bono, J S and Banerji, U 2018. Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer. Annals of Oncology 29 (9) , pp. 1918-1925. 10.1093/annonc/mdy245

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Abstract

Background We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76–21.25). Discussion In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution
Publisher: Oxford University Press (OUP): Policy A1 - Oxford Open Option F
ISSN: 0923-7534
Date of First Compliant Deposit: 17 January 2019
Date of Acceptance: 17 July 2018
Last Modified: 14 Nov 2019 16:34
URI: http://orca.cf.ac.uk/id/eprint/118502

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