A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.

BACKGROUND: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. PATIENTS AND METHODS: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. RESULTS: Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). CONCLUSIONS: This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.

Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled, flexible-dosage trial.

BACKGROUND: The objective of this randomized, double-blind, placebo-controlled study was to investigate the efficacy and safety of paroxetine in outpatients with generalized anxiety disorder (GAD). METHOD: Male and female outpatients 18 years and older who met DSM-IV criteria for GAD and had baseline scores of at least 20 on the Hamilton Rating Scale for Anxiety (HAM-A) were randomly assigned to treatment with paroxetine (20-50 mg/day) or placebo for 8 weeks. The primary efficacy variable was the mean change from baseline in the total score of the HAM-A. Additional key efficacy variables were the change from baseline in the scores of the HAM-A items anxious mood and tension, the anxiety subscale of the Hospital Anxiety and Depression Scale, and the Sheehan Disability Scale (SDS). The proportions of patients fulfilling response and remission criteria at week 8 were also determined. RESULTS: The intent-to-treat population included 324 patients. At week 8, compared with the placebo group (N = 163), the paroxetine group (N = 161) had a significantly greater reduction of GAD symptoms on all of the above-mentioned efficacy variables. On the HAM-A anxious mood item, which encompasses the cardinal symptoms of GAD, significantly greater efficacy was observed from week 1 and on the SDS significantly greater improvement was documented in the domain "social life" as early as week 4 for paroxetine compared with placebo. In both the last-observation-carried-forward and completer data sets, significantly greater proportions of paroxetine-treated patients achieved response or remission by week 8. Treatment with paroxetine was well tolerated, and the number and type of adverse events recorded in the paroxetine group correspond to the known safety profile of this medication. CONCLUSION: Paroxetine in doses of 20 to 50 mg once daily is effective in the treatment of patients with GAD. Improvement of core symptoms of GAD occurs early and is associated with significant reduction in disability after only 8 weeks of treatment.