Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer
Year: 2018
Type: article
Study design: Clinical Trial
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. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.
Source: Annals of Oncology
Authors: B. Basu, M.G. Krebs, R. Sundar, R.H. Wilson, J. Spicer, R. Jones, M. Brada, D.C. Talbot, N. Steele, A.H. Ingles Garces, W. Brugger, E.A. Harrington, J. Evans, E. Hall, H. Tovey, F.M. de Oliveira, S. Carreira, K. Swales, R. Ruddle, F.I. Raynaud, B. Purchase, J.C. Dawes, M. Parmar, A.J. Turner, N. Tunariu, S. Banerjee, J.S. de Bono, U. Banerji
Institutions: University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, The Christie NHS Foundation Trust, Institute of Cancer Research, National University Health System, Queen's University Belfast, Belfast City Hospital, King's College London, Guy's and St Thomas' NHS Foundation Trust, Velindre Cancer Centre, Cardiff University, University of Liverpool, Clatterbridge Cancer Centre NHS Foundation Trust, Oxford University Hospitals NHS Trust, Beatson West of Scotland Cancer Centre, University of Glasgow, AstraZeneca (United Kingdom), Royal Marsden NHS Foundation Trust, Royal Marsden Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,080
Funders: AstraZeneca, National Institute on Handicapped Research, King’s College London, Royal Marsden NHS Foundation Trust, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Cancer Research UK, National Institute for Health and Care Research, Public Health Agency, Christie NHS Foundation Trust, Imperial Experimental Cancer Medicine Centre, National Medical Research Council, Institute of Cancer Research
OpenAlex ID: W2888480300