دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer.
المؤلفون: Basu, B, Krebs, MG, Sundar, R, Wilson, RH, Spicer, J, Jones, R, Brada, M, Talbot, DC, Steele, N, Ingles Garces, AH, Brugger, W, Harrington, EA, Evans, J, Hall, E, Tovey, H, de Oliveira, FM, Carreira, S, Swales, K, Ruddle, R, Raynaud, FI, Purchase, B, Dawes, JC, Parmar, M, Turner, AJ, Tunariu, N, Banerjee, S, de Bono, JS, Banerji, U
المساهمون: Hall, Emma, Tovey, Holly, Carreira, Suzanne, Swales, Karen, Ruddle, Ruth, Raynaud, Florence, De Bono, Johann, Banerji, Udai
بيانات النشر: OXFORD UNIV PRESS
سنة النشر: 2018
المجموعة: The Institute of Cancer Research (ICR): Publications Repository
مصطلحات موضوعية: Humans, Carcinoma, Non-Small-Cell Lung, Ovarian Neoplasms, Lung Neoplasms, Benzamides, Paclitaxel, Morpholines, Pyrimidines, Ribosomal Protein S6 Kinases, Antineoplastic Combined Chemotherapy Protocols, Protein Kinase Inhibitors, Drug Administration Schedule, Maximum Tolerated Dose, Phosphorylation, Adult, Middle Aged, Female, Male, Response Evaluation Criteria in Solid Tumors, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2
الوصف: 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.
نوع الوثيقة: article in journal/newspaper
وصف الملف: Print; 1925; application/pdf
اللغة: English
تدمد: 0923-7534
1569-8041
العلاقة: Annals of oncology : official journal of the European Society for Medical Oncology, 2018, 29 (9), pp. 1918 - 1925; https://repository.icr.ac.uk/handle/internal/2264Test
DOI: 10.1093/annonc/mdy245
الإتاحة: https://doi.org/10.1093/annonc/mdy245Test
https://repository.icr.ac.uk/handle/internal/2264Test
حقوق: https://creativecommons.org/licenses/by/4.0Test
رقم الانضمام: edsbas.F4424177
قاعدة البيانات: BASE
الوصف
تدمد:09237534
15698041
DOI:10.1093/annonc/mdy245