Μετάβαση στο κύριο περιεχόμενο

! # Ola via Alexandros G.Sfakianakis on Inoreader

Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer.

Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer.

Invest New Drugs. 2017 Dec 01;:

Authors: Goldman JW, Rosen LS, Tolcher AW, Papadopoulos K, Beeram M, Shi P, Pitou C, Bell R, Kulanthaivel P, Zhang X, Fink A, Chan EM, Shahir A, Farrington D, Patnaik A

Abstract
Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalation), LY3007113 was administered orally every 12 h (Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-day cycle until the maximum tolerated dose (MTD) was reached. In part B (dose confirmation), patients received MTD. Safety, pharmacokinetics, pharmacodynamics, and tumor response data were evaluated. Results MTD was 30 mg Q12H. The most frequent treatment-related adverse events (>10%) were tremor, rash, stomatitis, increased blood creatine phosphokinase, and fatigue. Grade ≥ 3 treatment-related adverse events included upper gastrointestinal haemorrhage and increased hepatic enzyme, both occurring at 40 mg Q12H and considered dose-limiting toxicities. LY3007113 exhibited an approximately dose-proportional increase in exposure and time-independent pharmacokinetics after repeated dosing. Maximal inhibition (80%) of primary biomarker MAPK-activated protein kinase 2 in peripheral blood mononuclear cells was not reached, and sustained minimal inhibition (60%) was not maintained for 6 h after dosing to achieve a biologically effective dose (BED). The best overall response in part B was stable disease in 3 of 27 patients. Conclusions The recommended phase 2 dosage of LY3007113 was 30 mg Q12H. Three patients continued treatment after the first radiographic assessment, and the BED was not achieved. Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose.

PMID: 29196957 [PubMed - as supplied by publisher]



from ! ORL Sfakianakis via paythelady.61 on Inoreader http://ift.tt/2ntLdTm
via IFTTT

Σχόλια

Δημοφιλείς αναρτήσεις από αυτό το ιστολόγιο

Accessory Auricles: Systematic Review of Definition, Associated Conditions, and Recommendations for Clinical Practice

Abstract Accessory auricles are rare congenital abnormalities embryologically derived from the first branchial arch. Presentation may be variable with locations grouped into anatomical zones based on the frequency of location found in the literature. This study reviewed the papers between 1981 and 2017. Findings included an association with syndromes including Goldenhar, VACTERL, Treacher–Collins, Townes–Brocks, and Wolf–Hirschhorn. Based on histological and embryological evidence, the term "accessory auricle" is best used as an umbrella term to define this difference. Finally, indications are provided for imaging and laboratory investigations to guide the physician treating patients with accessory auricles. Address correspondence and reprint requests to Mark S. Lloyd, MPhil, FRCS(Plast), Department of Plastic Surgery, Autologous Ear Reconstruction Service, Birmingham Children's and Women's Hospital NHS Trust, 4th Floor, Ladywood House, Steelhouse Lane, Birmingham B4…

A Rare Complication After Septoplasty: Visual Loss Due to Right Retinal Artery Spasm

Abstract Septoplasty is a commonly used procedure for correcting septal cartilage deformities. Hemorrhage, abscesses, scaling, adhesions, and scar tissue are often seen after the operation of the septoplasty, but temporary or permanent visual loss due to local anesthetic use has been reported very rarely in the literature. The authors also aimed to present a female patient with retinal artery spasm in the right eye after septoplasty in this article. A 27-year-old female patient was admitted to the authors' clinic with long-standing nasal obstruction and postnasal drip. There was no feature in her history and also no sign other than nasal septal deviation on physical examination. The patient was informed about the operation and the operation was planned. Emergency eye consultation was requested after the patient said that the right eye of the patient had never seen in the postoperative wake-up hall. Examination by an ophthalmologist; mild exotropia and total loss of vision in the r…

Anti-Neutrophil Cytoplasmic Antibody-Negative Central Nervous System Granulomatosis With Polyangiitis and Its Clinical Characteristics

Abstract Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis occasionally affecting central nervous system (CNS), and GPA patients with initial CNS symptoms are even rarer, whose diagnosis is further confused by an absence of positive antineutrophil cytoplasmic antibody. The authors described the characteristics of antineutrophil cytoplasmic antibody -negative GPA with CNS onset in a patient and discussed on its management, which may contribute to future diagnosis and treatment of patients with similar conditions. Address correspondence and reprint requests to Dr Yongming Qiu, MD, PhD, Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200127, China; E-mail: qiuzhoub@126.com; Dr Longtian Chen, MD, Department of Rheumatology, Longyan First Hospital Affiliated to Fujian Medical University, Fujian Province, China; E-mail: LT_chen@163.com Received 20 July, 2017 Accepted 24 August, 2017 The authors report no …