A phase Ib trial of combined PKC and MEK inhibition with sotrastaurin and binimetinib in patients with metastatic uveal melanoma.

Background: Uveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK.

Method: We conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358).

Genomic Profiling of Metastatic Uveal Melanoma and Clinical Results of a Phase I Study of the Protein Kinase C Inhibitor AEB071.

Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Patients with metastatic UM ( = 153) were treated with AEB071 in a phase I, single-arm study.

Functional Decline is Associated with Hopelessness in Amyotrophic Lateral Sclerosis (ALS).

Objective: To determine the relationships between hopelessness, depression, quality of life, and disease progression in ALS.

Methods: Hopelessness and depression were assessed prospectively in a cohort of people with ALS using the Beck Hopelessness scale (BHS) and the ALS Depression Inventory (ADI-12), respectively. ALS Specific Quality of Life and measures of functional status (ALSFRS-R and forced vital capacity) were collected.

Analysis of start-up, retention, and adherence in ALS clinical trials.

Objective: To investigate predictors of trial start-up times, high attrition, and poor protocol adherence in amyotrophic lateral sclerosis (ALS) trials.

Methods: Retrospective analysis of start-up times, retention, and protocol adherence was performed on 5 clinical studies conducted by the Northeast ALS Consortium and 50 ALS clinical trials identified by PubMed search. Predictors of start-up times were estimated by accelerated failure time models with random effects.

Oral repeated-dose toxicity studies of coenzyme Q10 in beagle dogs.

To support phase III testing of coenzyme Q10 (CoQ₁₀) in humans, we conducted pharmacokinetic and toxicology studies in beagle dogs. Following single gavage administration of CoQ₁₀ at 600, 1200, 1800, or 2400 mg/kg per d no obvious dose response was observed in maximum concentration (C(max)) or area under the curve (AUC) versus time curve at the 3 highest dosages. In a repeated-dose study of CoQ₁₀ at 600, 1200, 1800, or 2400 mg/kg per d for 4 weeks, CoQ₁₀ reached steady state in plasma by 2 weeks at all dosages.

Depression in amyotrophic lateral sclerosis.

Depression is an under-recognized comorbidity associated with amyotrophic lateral sclerosis (ALS). The goals of this study were to prospectively estimate the prevalence of depression and other ALS related symptoms and to study the impact of depression on enrollment in research studies. One hundred and twenty-seven people with ALS completed the ALS Depression Inventory (ADI-12) and answered questions about ALS related symptoms and research study enrollment preferences.