1. Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer
- Author
-
J.S. de Bono, Joseph R. Evans, Wolfram Brugger, Susana Carreira, Matthew G Krebs, Elizabeth A. Harrington, Ruth Ruddle, Beth Purchase, Robert H. Jones, Mahesh K. B. Parmar, Alison Turner, Karen E Swales, Udai Banerji, F.M. de Oliveira, Michael Brada, Holly Tovey, Bristi Basu, Emma Hall, Richard H. Wilson, Susana Banerjee, J.C. Dawes, Florence I. Raynaud, Nina Tunariu, James Spicer, N. Steele, Denis Talbot, A.H. Ingles Garces, Raghav Sundar, Basu, Bristi [0000-0002-3562-2868], and Apollo - University of Cambridge Repository
- 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 - 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.
- Published
- 2018