Sok Won Kim

A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)

BACKGROUND KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. PATIENTS AND METHODS Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. RESULTS One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. CONCLUSION Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. CLINICALTRIALSGOV REGISTRATION NUMBER NCT01362296.

Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer patients after failure of gefitinib treatment

BACKGROUND Both gefitinib and erlotinib are reversible epidermal growth factor receptor tyrosine kinase inhibitors, but they have somewhat different pharmacological properties. We conducted a phase II study of erlotinib after failure of gefitinib treatment in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with advanced/metastatic NSCLC who had shown disease progression on gefitinib treatment were treated with erlotinib 150 mg/day until disease progression or intolerable toxicity. RESULTS Between September 2006 and January 2008, a total of 23 patients were enrolled and all were assessable for response and toxicity. All patients were never smokers and all but one had adenocarcinoma. Of these 23 patients, one had a partial response and one stable disease, resulting in an objective response rate of 4.3% and a disease control rate of 8.7%. These two patients benefited from erlotinib for 6.2 months and 7.8 months, respectively; both had also benefited from prior gefitinib therapy. The most common toxic effects were skin rash and diarrhea. CONCLUSION Erlotinib should not be given routinely after failure of gefitinib treatment, but can be an option for more highly selected subsets, especially those who had benefited from prior gefitinib treatment. Identification of molecular markers in tumors is important to understand and overcome acquired resistance to gefitinib.

A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study)

BACKGROUND A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). METHODS A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. RESULTS Enrollment was stopped when 307 patients were randomized, following the Safety Review Committees recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥ 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). CONCLUSIONS This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR. TRIAL REGISTRATION NUMBER NCT01377376.

Metal-insulator transition without structural phase transition in V2O5 film

Spectroscopic ellipsometry and x-ray diffraction are used to investigate the metal-insulator transition in V2O5 films. Below and above Tc no significant change in the (001) peak is observed, but both n and k spectra undergo remarkable changes over the entire photon energy range. The SE and XRD results indicate that the V2O5 film undergoes a MIT without a structural phase transition near 280 °C. Further the MIT is confirmed by measurement of the resistance with temperature.

High-Temperature Fiber Optic Sensor Using a Grating on an Angled Fiber Tip

In order to achieve a more stable fiber-optic temperature sensor in a high temperature range, a grating was produced by lithography and dry etching on the 45° angled fiber tip to diffract a portion of the incident light back to the fiber axis and to interfere with the light which is totally reflected from the angled fiber tip. The performance was investigated in the range of the room temperature to 1100°C for s- and p-polarized input beams and then analyzed by the parameter estimation technique. The result shows that the variation of signal intensity is dependent on the input polarization state and that the phase change from the thermo-optic and thermal expansion coefficients must be treated as a linear function of temperature.

Characterization of micellar film morphologies of semifluorinated block copolymers by AFM

The micellar morphologies of well-defined amphiphilic block copolymers composed of 1H,1H-dihydroperfluorooctyl methacrylate (FOMA) and ethylene oxide (EO) blocks with different chain lengths were effectively investigated by using tapping mode-atomic force microscopy (TM-AFM). By spin-casting chloroform solutions, well-ordered spherical micellar films could be obtained for poly(FOMA(10k)-b-EO(10k)) and poly(FOMA(20k)-b-EO(20k)) copolymers. The atomic force microscopy (AFM) height and phase image analysis indicated that dark regions of the micelles corresponded to PEO blocks and the light regions were for PFOMA blocks. The spherical micelles with PEO corona and PFOMA core were also identified by transmission electron microscopy (TEM) and X-ray photoelectron spectrometer (XPS) analysis. The core diameters of the block-copolymer aggregates were 20 nm for poly(FOMA(10k)-b-EO(10k)) and 30 nm for poly(FOMA(20k)-b-EO(20k)) by TM-AFM, whereas slightly lower values of 17 and 26 nm were obtained from TEM. A detailed study on the inverted morphological change observed in the micelles films after annealing above glass transition temperature (T(g)) was also presented.

Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis

BACKGROUND This preplanned subset analysis of the phase III MONET1 study aimed to determine whether motesanib combined with carboplatin/paclitaxel (C/P) would result in improved overall survival (OS) versus chemotherapy alone, in a subset of Asian patients with nonsquamous nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with nonsquamous NSCLC (stage IIIB/IV or recurrent) and no prior systemic therapy for advanced disease were randomized to IV carboplatin (AUC, 6 mg/ml min) and paclitaxel (200 mg/m2) for up to six 3-week cycles, plus either oral motesanib 125 mg q.d. or placebo. Primary end point was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS Two hundred twenty-seven Asian patients from MONET1 were included in this descriptive analysis. Median OS was 20.9 months in the motesanib plus C/P arm and 14.5 months in the placebo plus C/P arm (P=0.0223); median PFS was 7.0 and 5.3 months, respectively, (P=0.0004); and ORR was 62% and 27%, respectively, (P<0.0001). Grade≥3 adverse events were more common in the motesanib plus C/P arm versus placebo plus C/P (79% versus 61%). CONCLUSION In this preplanned subset analysis of Asian patients with nonsquamous NSCLC, motesanib plus C/P significantly improved OS, PFS, and ORR versus placebo plus C/P. CLINICAL TRIAL NUMBER NCT00460317.

Optical properties for the Mott transition in VO2

The relationship between the first-order metal-insulator transition (MIT) and the structural phase transition (SPT) in VO2 film is analyzed by dielectric function, optical conductivity, plasma energy, and electrical conductivity. The MIT and SPT temperatures in VO2 films were approximately 68 and 75 °C, respectively, with an intermediate phase existing between 68 and 75 °C. The optical and electrical results indicate that the first-order MIT in VO2 films is not driven by the SPT.

Statistical Analysis of Fluorescence Correlation Spectroscopy of Ultra Low Concentration Molecules with a Confocal Microscope

In this study, we simulated a statistical model of FCS (fluorescence correlation spectroscopy) based on a Poisson process to understand and explain observations of the experiment performed on molecules of ultra-low concentration by the home-built laser- scanning confocal microscope. The statistical model confirmed that the relative mean square amplitude of fluctuations is shown to be inversely proportional to the average number of molecules, even in the ultra-low concentration, if some conditions are satisfied. Signal-to-noise ratio and the variability of dwelling time under the confocal volume were found to be effective conditions for the experiment.

Temperature dependence of the interband transition in a V2O5 film

The temperature dependence of the interband transition in an α-V2O5 film was investigated using absorption and photoluminescence spectral measurements at a temperature range of 10–300 K. Transmission measurements in the experimental temperature range indicate that the α-V2O5 film has two distinct interband transitions, implying indirect and direct transitions. This result was confirmed by spectroscopic ellipsometry. The blue shift of both the transitions in the α-V2O5 film with decreasing temperature was explained by a reduction in the lattice-dilatation effect and the electron-phonon interaction. The PL measurements in the experimental temperature range showed that the emission near 530 nm is due to the indirect transition in the α-V2O5 film.