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

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

doi:10.1093/annonc/mdy245

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

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

Division of Cancer Sciences (L5)

Cambridge University Hospitals NHS Foundation Trust
National University Health Systems
Queen's University Belfast
Oxford University Hospitals NHS Trust
University of Glasgow
The Institute of Cancer Research (University of London)
AstraZeneca
The Royal Marsden NHS Foundation Trust
University of Liverpool
King's College London
Guy's & St Thomas' NHS Foundation Trust
Cardiff University
Velindre Cancer Centre

Research output: Contribution to journal › Article › peer-review

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/m 2) 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/m 2 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

Original language	English
Pages (from-to)	1918-1925
Number of pages	8
Journal	Annals of Oncology
Volume	29
Issue number	9
Early online date	17 Jul 2018
DOIs	https://doi.org/10.1093/annonc/mdy245
Publication status	Published - 1 Sept 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

combination therapy
m-TORC1/m-TORC2 inhibitor
ovarian cancer
phase 1
squamous non-small-cell lung cancer

Research Highlights, Institutes and Platforms

Manchester Cancer Research Centre

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10.1093/annonc/mdy245Licence: CC BY

https://academic.oup.com/annonc/article/29/9/1918/5055047

Cite this

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., ... 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), 1918-1925. https://doi.org/10.1093/annonc/mdy245

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

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/m 2) 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/m 2 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",

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author = "B Basu and Krebs, \{M G\} and R Sundar and Wilson, \{R H\} and J Spicer and R Jones and M Brada and Talbot, \{D C\} and N Steele and \{Ingles Garces\}, \{A H\} and W Brugger and Harrington, \{E A\} and J Evans and E Hall and H Tovey and \{De Oliveira\}, \{F M\} and S Carreira and K Swales and R Ruddle and Raynaud, \{F I\} and B Purchase and Dawes, \{J C\} and M Parmar and Turner, \{A J\} and N Tunariu and S Banerjee and \{De Bono\}, \{J S\} and U Banerji",

year = "2018",

month = sep,

day = "1",

doi = "10.1093/annonc/mdy245",

language = "English",

volume = "29",

pages = "1918--1925",

journal = "Annals of Oncology",

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}

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 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

TY - JOUR

T1 - Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer

AU - Basu, B

AU - Krebs, M G

AU - Sundar, R

AU - Wilson, R H

AU - Spicer, J

AU - Jones, R

AU - Brada, M

AU - Talbot, D C

AU - Steele, N

AU - Ingles Garces, A H

AU - Brugger, W

AU - Harrington, E A

AU - Evans, J

AU - Hall, E

AU - Tovey, H

AU - De Oliveira, F M

AU - Carreira, S

AU - Swales, K

AU - Ruddle, R

AU - Raynaud, F I

AU - Purchase, B

AU - Dawes, J C

AU - Parmar, M

AU - Turner, A J

AU - Tunariu, N

AU - Banerjee, S

AU - De Bono, J S

AU - Banerji, U

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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/m 2) 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/m 2 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

AB - 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/m 2) 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/m 2 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

KW - combination therapy

KW - m-TORC1/m-TORC2 inhibitor

KW - ovarian cancer

KW - phase 1

KW - squamous non-small-cell lung cancer

UR - https://www.scopus.com/pages/publications/85054307995

U2 - 10.1093/annonc/mdy245

DO - 10.1093/annonc/mdy245

M3 - Article

C2 - 30016392

SN - 0923-7534

VL - 29

SP - 1918

EP - 1925

JO - Annals of Oncology

JF - Annals of Oncology

IS - 9

ER -

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

Abstract

UN SDGs

Keywords

Research Highlights, Institutes and Platforms

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