A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.     

Touring Arkansas: A Statewide Project to Instruct Nurses and Patient Educators on Consumer Health Resources

Abstract

This article follows up a pilot project to help educate local nurses and patient educators on freely available consumer health resources. The Outreach Coordinator and Clinical Librarian at an academic medical center created a one-hour in-person and online class with continuing education credit and an online guide. Nurses frequently act as patient educators at the bedside and are therefore an important target for consumer health education. While nurses in an urban setting may have more access to educational opportunities, these opportunities are needed even more in rural settings. Librarians can obtain funding to travel and teach classes at rural community hospitals.     

No Influence of the Fat Mass and Obesity-Associated Gene rs9939609 Single Nucleotide Polymorphism on Blood Lipids in Young Males

The fat mass and obesity-associated gene (FTO) rs9939609 A-allele is linked to obesity and dyslipidemia, yet the independent influence of this polymorphism on blood lipids remains equivocal. We examined the influence of the FTO rs9939609 polymorphism on fasting and postprandial blood lipids in individuals homozygous for the risk A-allele or T-allele with similar anthropometric and demographic characteristics. 12 AA and 12 TT males consumed a standardized meal after fasting overnight. Blood samples were collected at baseline (−1.5 h), before the meal (0 h), and for five hours postprandially to measure lipid, glucose, and insulin concentrations. Time-averaged total area under the curve (TAUC) values (0–5 h) were calculated and compared between genotypes. Fasting triacylglycerol (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, non-esterified fatty acid (NEFA), glucose, and insulin concentrations were similar between groups (p ≥ 0.293). TAUC for TG was similar in AAs and TTs (95% confidence interval (CI) −0.52 to 0.31 mmol/L/h; p = 0.606). Likewise, TAUC values were similar for NEFA (95% CI −0.04 to 0.03 mmol/L/h; p = 0.734), glucose (95% CI −0.41 to 0.44 mmol/L/h; p = 0.951), and insulin (95% CI −6.87 to 2.83 pmol/L/h; p = 0.395). Blood lipids are not influenced by the FTO rs9939609 polymorphism, suggesting the FTO-dyslipidemia link is mediated by adiposity and weight management is important in preventing FTO-related lipid variations.