Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer |
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| Institution: | 1. Department of Oncology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge;2. Manchester Academic Health Science Centre, The University of Manchester and The Christie NHS Foundation Trust, Manchester;3. Drug Development Unit, The Institute of Cancer Research and The Royal Marsden, London, UK;4. Department of Haematology-Oncology, National University Health System, Singapore;5. Centre for Cancer Research and Cell Biology, Queen’s University Belfast and Belfast City Hospital, Belfast;6. School of Cancer and Pharmaceutical Sciences, King’s College London and Guy''s and St Thomas’ NHS Foundation Trust, London;7. Cardiff University and Velindre Cancer Centre, Cardiff;8. University of Liverpool and Clatterbridge Cancer Centre NHS Foundation Trust, Wirral;9. Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford;10. University of Glasgow and Beatson West of Scotland Cancer Centre, Glasgow;11. Oncology, IMED Biotech Unit AstraZeneca, Cambridge;12. Clinical Trials and Statistics Unit, The Institute of Cancer Research, London;13. Division of Clinical Studies, The Institute of Cancer Research, London;14. Division of Cancer Therapeutics, The Institute of Cancer Research, London;15. Department of Gynae-Oncology, The Royal Marsden, London, UK |
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| Abstract: | BackgroundWe 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 methodsIn 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.ResultsThe 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).DiscussionIn 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 registrationClinicialTrials.gov identifier: CNCT02193633 |
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