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Objectives: This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations., Methods: Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m 2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m 2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens., Results: The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events-most commonly diarrhea, nausea, and fatigue-were manageable., Conclusions: Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Assessing the effects of new chemical entities on respiratory function in animal models is an essential component of preclinical drug safety evaluation. Methods currently available for measuring ventilatory parameters in conscious dogs generally utilize a plethysmograph chamber or a face mask equipped with a pneumotachograph attached to the snout of the animal. These methods require restraint and allow for only short, periodic measurements. Because of these limitations, respiratory inductive plethysmography (RIP) was evaluated as a possible new methodology that will allow for continuous monitoring of respiratory parameters in non-restrained dogs for extended periods of time., Methods: Straps containing inductive coils were placed around the thorax and abdomen to measure thoracic and abdominal excursions. The straps were contained within a protective jacket that was placed on the dogs and the electrical signals from the inductive coils were transmitted by telemetry to a receiver. The data were acquired and analyzed using the Vivometrics(R) LifeShirt(R) PreClinical System. Because postural changes can alter tidal volume measurements using RIP, the jacket also contained an accelerometer that was used to record postural changes during ventilatory measurements., Results: Measurement of ventilatory parameters in dogs following manual placement in different positions (e.g., standing, sitting, lateral recumbent) or during the different postures in non-restrained dogs demonstrated that changes in posture had only a minimal influence (