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/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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Benzamides/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/pathology , Morpholines/administration & dosage , Ovarian Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzamides/adverse effects , Benzamides/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/pathology , Drug Administration Schedule , Female , Humans , Lung Neoplasms/drug therapy , Male , Maximum Tolerated Dose , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors , Middle Aged , Morpholines/adverse effects , Morpholines/pharmacokinetics , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Phosphorylation/drug effects , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Response Evaluation Criteria in Solid Tumors , Ribosomal Protein S6 Kinases/metabolismABSTRACT
OBJECTIVES: The aim of this was to compare the performance of the Framingham, Systematic Coronary Risk Evaluation (SCORE) and Prospective Cardiovascular Munster (PROCAM) scoring systems in the risk assessment of HIV-infected patients with no overt vascular disease. METHODS: A cross-sectional study of 220 HIV-infected patients was conducted at the outpatient clinic of a referral and training centre in infectious and parasitic diseases in Belo Horizonte, Brazil. The Framingham, SCORE and PROCAM equations were calculated. Patients were classified as having low, moderate or high risk, which according to the Framingham and PROCAM equations corresponded to < 10%, 10-20% and > 20% respectively, and according to SCORE corresponded to < 3%, 3-4% and > or = 5% respectively. Cohen's kappa coefficient was used to assess agreement between the methods. RESULTS: Of a total of 220 HIV-infected patients, 56 were antiretroviral (ARV)-naïve while 164 had already been treated with ARV. The prevalence of patients with a high 10-year cardiovascular risk was 3.7%, 2.5% and 1.9% according to the Framingham, PROCAM and SCORE equations respectively. The degree of agreement was moderate between the Framingham and PROCAM risk estimates (kappa = 0.433; p < 0.001), poor-to-fair between the Framingham and SCORE estimates (kappa = 0.220; p < 0.001) and moderate between the PROCAM and SCORE systems (kappa = 0.478; p < 0.001). CONCLUSIONS: There are differences in risk assessment and in the identification of high risk individuals between the three risk functions under evaluation and only a prospective study will be capable of assessing which offers the best current sensitivity, specificity and predictive values for the population under investigation.
