A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer.

PURPOSE: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. RESULTS: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. CONCLUSIONS: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368-76. ©2015 AACR.

Can liquorice extract and herbal solution prevent colonic mucosa damage caused by robenacoxib in dogs?

UNLABELLED: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in animals, especially in dogs, to manage pain due to inflammatory disease. This study investigated whether plant drugs can prevent mucosal injury induced by robenacoxib. We used fifteen healthy beagle dogs (7 male and 8 female) aged 4 months, weighing 4.2-5.1 kg at the beginning of the study. Endoscopy and biopsy of the colon were performed before and on the 21 day treatment with robenacoxib (1), robenacoxib, herbal solution with liquorice extract (2), placebo - an empty capsule (3). There were 5 animals in each group. The greatest microscopic damage in the colon was observed in animals which received robenacoxib. Plant drug administration reduced the severity of lesions in the colon when administered with robenacoxib (ARI = - 0.15). CONCLUSION: concurrent administration of liquorice extract and plant solution with robenacoxib was associated with significant decreased severity of the robenacoxib-induced colonic mucosal lesions.