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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
- Source :
- ANNALS OF ONCOLOGY, 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 & 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, vol. 29, no. 9, pp. 1918-1925 . https://doi.org/10.1093/annonc/mdy245, Annals of Oncology
- Publication Year :
- 2018
-
Abstract
- Background: \ud 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.\ud \ud Patients and methods: \ud 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.\ud \ud Results: \ud 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).\ud \ud Discussion: \ud 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.\ud \ud Clinical trial registration: \ud ClinicialTrials.gov identifier: CNCT02193633.
- Subjects :
- 0301 basic medicine
Male
Lung Neoplasms
medicine.medical_treatment
m-TORC1/m-TORC2 inhibitor
Phases of clinical research
Gastroenterology
combination therapy
chemistry.chemical_compound
0302 clinical medicine
Carcinoma, Non-Small-Cell Lung
Antineoplastic Combined Chemotherapy Protocols
squamous non-small cell lung cancer
Phosphorylation
Ovarian Neoplasms
Manchester Cancer Research Centre
Hematology
Middle Aged
squamous non-small-cell lung cancer
ovarian cancer
Oncology
Paclitaxel
Response Evaluation Criteria in Solid Tumors
030220 oncology & carcinogenesis
Benzamides
Early Drug Development
Female
Adult
medicine.medical_specialty
Maximum Tolerated Dose
Morpholines
Mechanistic Target of Rapamycin Complex 2
Mechanistic Target of Rapamycin Complex 1
Drug Administration Schedule
03 medical and health sciences
Internal medicine
medicine
Mucositis
Humans
Progression-free survival
Lung cancer
Protein Kinase Inhibitors
Chemotherapy
business.industry
Ribosomal Protein S6 Kinases
ResearchInstitutes_Networks_Beacons/mcrc
Original Articles
medicine.disease
030104 developmental biology
Pyrimidines
chemistry
phase 1
Ovarian cancer
business
Subjects
Details
- Language :
- English
- ISSN :
- 09237534
- Database :
- OpenAIRE
- Journal :
- ANNALS OF ONCOLOGY, 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 & 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, vol. 29, no. 9, pp. 1918-1925 . https://doi.org/10.1093/annonc/mdy245, Annals of Oncology
- Accession number :
- edsair.doi.dedup.....751863d1aac996757bef829196cc6b21