The First-in-Human Study of the Hydrogen Sulfate (Hyd-Sulfate) Capsule of the MEK1/2 Inhibitor AZD6244 (ARRY-142886): A Phase I Open-Label Multicenter Trial in Patients with Advanced Cancer

Contains fulltext : 87826timmer-bonte.pdf (publisher's version ) (Closed access)PURPOSE: In part A, the aim was to define the maximum tolerated dose (MTD) of the hydrogen sulfate (Hyd-Sulfate) oral capsule formulation of the mitogen-activated protein kinase kinase inhibitor AZD6244 (ARRY-142886). In part B, the aim was to compare the pharmacokinetic profile of the new Hyd-Sulfate capsule with the initial AZD6244 free-base suspension and further characterize the pharmacodynamic profile and efficacy of the new formulation. EXPERIMENTAL DESIGN: In part A, 30 patients received escalating doses of AZD6244 Hyd-Sulfate twice daily. In part B, 29 patients were randomized to a single dose of the Hyd-Sulfate capsule or free-base suspension, followed by a washout, then a single dose of the alternative formulation. Patients received the Hyd-Sulfate capsule twice daily at MTD of part A thereafter. RESULTS: The MTD of the Hyd-Sulfate capsule was 75 mg twice daily. Dose limiting toxicities were Common Terminology Criteria for Adverse Events grade 3 acneiform rash and pleural effusion. Fatigue (65.7%) and acneiform dermatitis (60.0%) were the most frequent adverse events at the MTD. Based on area under curve(0-24), exposure of the 75 mg Hyd-Sulfate capsule relative to the 100 mg free-base suspension was 197% (90% confidence interval, 161-242%). Pharmacodynamic analysis showed that inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced extracellular signal-regulated kinase phosphorylation in peripheral blood lymphocytes was related to plasma concentrations of AZD6244, with an estimated IC(50) of 352 ng/mL and maximum inhibition (E(max)) of approximately 91%, showing target inhibition. A patient with metastatic melanoma bearing a V600E BRAF mutation achieved a complete response persisting after 15 months of therapy. CONCLUSIONS: The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials

Nonclassical properties of generalized four-photon coherent states

We proposed a scheme to generate new class of even(odd) compass states (specific superpositions of Wigner cat states [A. Dehghani et al., Ann. Phys. 362, 659 (2015)]), in the presence of the parity deformed Jaynes–Cummings Hamiltonian [A. Dehghani et al., Sci. Rep. 6, 38069 (2016)] describing a coupled system comprising a two-level atom and a cavity field assisted by a continuous external classical field. Particular attention was given to analyze their non-classical properties through of the Mandel’s parameter and quadrature squeezing. The Wigner compass states (WCSs) are compared with the ordinary ones, when the Wigner parameter becomes zero. Meanwhile generalized photon added compass states (PAWCSs) were introduced, by excitations of a newly introduced WCSs. Along with statistical analysis of latter case, a new theoretical framework for preparing them is suggested

Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (\ue2\u89\ua550% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks

Exploring cosmic origins with CORE: Survey requirements and mission design

Future observations of cosmic microwave background (CMB) polarisation have the potential to answer some of the most fundamental questions of modern physics and cosmology, including: what physical process gave birth to the Universe we see today? What are the dark matter and dark energy that seem to constitute 95% of the energy density of the Universe? Do we need extensions to the standard model of particle physics and fundamental interactions? Is the ΛCDM cosmological scenario correct, or are we missing an essential piece of the puzzle? In this paper, we list the requirements for a future CMB polarisation survey addressing these scientific objectives, and discuss the design drivers of the COREmfive space mission proposed to ESA in answer to the "M5" call for a medium-sized mission. The rationale and options, and the methodologies used to assess the mission's performance, are of interest to other future CMB mission design studies. COREmfive has 19 frequency channels, distributed over a broad frequency range, spanning the 60–600 GHz interval, to control astrophysical foreground emission. The angular resolution ranges from 2' to 18', and the aggregate CMB sensitivity is about 2 μK⋅arcmin. The observations are made with a single integrated focal-plane instrument, consisting of an array of 2100 cryogenically-cooled, linearly-polarised detectors at the focus of a 1.2-m aperture cross-Dragone telescope. The mission is designed to minimise all sources of systematic effects, which must be controlled so that no more than 10−4 of the intensity leaks into polarisation maps, and no more than about 1% of E-type polarisation leaks into B-type modes. COREmfive observes the sky from a large Lissajous orbit around the Sun-Earth L2 point on an orbit that offers stable observing conditions and avoids contamination from sidelobe pick-up of stray radiation originating from the Sun, Earth, and Moon. The entire sky is observed repeatedly during four years of continuous scanning, with a combination of three rotations of the spacecraft over different timescales. With about 50% of the sky covered every few days, this scan strategy provides the mitigation of systematic effects and the internal redundancy that are needed to convincingly extract the primordial B-mode signal on large angular scales, and check with adequate sensitivity the consistency of the observations in several independent data subsets. COREmfive is designed as a "near-ultimate" CMB polarisation mission which, for optimal complementarity with ground-based observations, will perform the observations that are known to be essential to CMB polarisation science and cannot be obtained by any other means than a dedicated space mission. It will provide well-characterised, highly-redundant multi-frequency observations of polarisation at all the scales where foreground emission and cosmic variance dominate the final uncertainty for obtaining precision CMB science, as well as 2' angular resolution maps of high-frequency foreground emission in the 300–600 GHz frequency range, essential for complementarity with future ground-based observations with large telescopes that can observe the CMB with the same beamsize