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Study Design A controlled laboratory study, with a single-blind, block-randomization crossover design. Objectives To compare the electrically elicited knee extensor torque produced by 3 clinically available waveforms: 2500-Hz burst-modulated alternating current (BMAC), 1000-Hz BMAC, and 1000-Hz burst-modulated biphasic square-wave pulsed current (BMBPC). Background Neuromuscular electrical stimulation (NMES) is the therapeutic use of electrical current to strengthen muscle. Muscle torque produced by NMES is limited by discomfort. Methods The knee extensor maximal volitional isometric torque (KEMVIT) of 33 able-bodied participants (18 female) was measured and used to normalize the electrically elicited knee extensor torque to produce a percent of KEMVIT (%KEMVIT). Electrically elicited isometric knee extensor torque was measured in response to each of the waveforms at the participants' maximum tolerance. Results The average maximum tolerated stimulation produced 32.0 ± 16.7 %KEMVIT with 2500-Hz BMAC, 38.2 ± 18.4 %KEMVIT with 1000-Hz BMAC, and 42.2 ± 17.1 %KEMVIT with 1000-Hz BMBPC. Tukey honest significant difference (HSD) post hoc testing revealed a statistically significant difference between 2500-Hz BMAC and 1000-Hz BMAC (P = .046), and between 2500-Hz BMAC and 1000-Hz BMBPC (P.001). No statistically significant difference was found between 1000-Hz BMAC and 1000-Hz BMBPC (P = .267). Conclusion For eliciting maximum knee extensor muscle torque, 1000-Hz BMBPC and 1000-Hz BMAC were similarly effective, and 2500-Hz BMAC was less effective. J Orthop Sports Phys Ther 2018;48(3):217-224. Epub 19 Dec 2017. doi:10.2519/jospt.2018.7601.

Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. The objective of this pivotal study was to assess the bioequivalence of a single intravenous infusion of rolapitant versus a single oral dose of rolapitant. In this randomized, open-label phase 1 study, healthy volunteers were administered rolapitant as a 180-mg oral dose or a 30-minute 166.5-mg intravenous infusion. Blood samples for pharmacokinetic analysis were collected predose and at points up to 912 hours postdose. Criteria for bioequivalence of the intravenous dose versus the oral dose were met if the 90% confidence intervals (CIs) for the ratios of the geometric least-squares means (GLSMs) for the area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t ) and AUC from time 0 extrapolated to infinity (AUC0-∞ ) for rolapitant were within 0.80-1.25. Mean rolapitant systemic exposure and half-lives were similar in the oral (n = 62) and intravenous (n = 61) rolapitant groups. The 90%CIs of the ratio of GLSMs were within the 0.80-1.25 range for AUC0-t (0.94-1.09) and AUC0-∞ (0.93-1.10). The incidence of treatment-emergent adverse events, all mild or moderate in severity, was similar in the intravenous and oral groups. A 166.5-mg intravenous infusion of rolapitant met the bioequivalence criteria based on AUC to a 180-mg oral dose and was well tolerated.

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. Four open-label phase 1 studies evaluated the safety and drug-drug interactions of a single dose of rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral digoxin (0.5 mg) or sulfasalazine (500 mg), probe substrates for the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. Administration of intravenous rolapitant with the substrates did not result in clinically significant effects on digoxin and sulfasalazine pharmacokinetics. In contrast, peak concentration and area under the curve for last quantifiable plasma concentrations increased by 71% (geometric mean ratio [GMR], 1.71; 90% confidence interval [CI], 1.49-1.95) and 30% (GMR, 1.30; 90%CI, 1.19-1.42), respectively, when rolapitant was coadministered orally with digoxin compared with digoxin alone; they increased by 140% (GMR, 2.40; 90%CI, 2.02-2.86) and 127% (GMR, 2.27; 90%CI, 1.94-2.65), respectively, when rolapitant was given orally with sulfasalazine compared with sulfasalazine alone. Adverse events were mild to moderate in severity in the absence or presence of rolapitant. There were no abnormal clinical laboratory or electrocardiogram findings. Thus, whether administered orally or intravenously, rolapitant was safe and well tolerated. Patients taking oral rolapitant with P-gp and BCRP substrates with a narrow therapeutic index should be monitored for potential adverse events; although increased plasma concentrations of these substrates may raise the risk of toxicity, they are not contraindicated.

Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers. Methods: In this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics. Results: TSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3–4 treatment-emergent adverse events occurred in 3.2–6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease. Conclusions: At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued, This clinical trial was funded by TESARO

The Fellowship Directors Forum, a special interest group of the American Academy of Hospice and Palliative Medicine (AAHPM) initiated an assessment of the needs of directors of fellowship programs in the emerging specialty of hospice and palliative care. One major finding, which may contribute to understanding the needs of other new disciplines, is that directors come into this role with clinical and teaching experience, but lacking administrative, educational, and management skills perceived as necessary to success. A study team collected data from current and former fellowship directors across the United States using an online survey and telephone interviews. The survey was sent to 60 current and former directors, with a 60% response rate, and 16 randomly selected directors were interviewed. Results showed that directors believe development of an outcome-based standardized curriculum is vitally important to advancement of the field, and that this should be developed collaboratively through the Forum. Although directors were confident of their own clinical and teaching skills, directors identified a lack of adequate training and experience in several management and educational skill areas critical to running a successful fellowship program. The study team made several recommendations: develop models from parts of existing programs that can be incorporated into a standardized curriculum to meet Accreditation Council of Graduate Medical Education (ACGME) requirements; provide workshops and toolkits for new directors to address the lack of management and educational skills; and establish new communication methods through more or longer forum meetings, a dedicated website, and an online discussion group.

Introduction: Rolapitant is a selective and long acting NK-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting (CINV). In vitro results indicated rolapitant mildly inhibited cytochrome P450 (CYP450) enzymes (2D6/2C9/2C19/2B6/2C8) at high concentrations (IC50s > 7 μM). The major metabolite SCH720881 did not inhibit these CYP enzymes. This study aimed to 1) evaluate the effects of rolapitant on the pharmacokinetics (PK) of CYP probe substrates (dextromethorphan [DET] for CYP2D6, tolbutamide [TOL] for CYP2C9, omeprazole [OMP] for CYP2C19, efavirenz [EFA] for CYP2B6 and repaglinide [REP] for CYP2C8), and 2) evaluate the safety and tolerability of rolapitant co-administered with these substrates in healthy subjects. Methods: This was an open-label, multi-part drug-drug interaction study in cohorts of 20 to 26 healthy subjects of orally-administered CYP probe substrates (Part-A: 30 mg DET; Part-B: 500 mg TOL plus 40 mg OMP; Part-C: 600 mg EFA; Part-D: 0.25 mg REP) in the absence and presence of single oral dose 180 mg rolapitant. Blood samples for determination of plasma concentration of CYP substrates and relevant metabolites were collected during 3 dosing periods in each part: 1) Period-1: CYP probe substrate alone as baseline; 2) Period-2: CYP probe substrate plus rolapitant concomitantly after a washout of probe given in Period 1 to evaluate the potential impact of rolapitant on probe substrate; and 3) Period-3: CYP probe substrate alone 7 days after the concomitant dose in Period-2 (approximating the peak time of metabolite SCH720881) to evaluate the impact of metabolite/rolapitant on probe substrate. Results: Rolapitant inhibited CYP2D6 following concomitant dose (Period-2) and 7 days after concomitant dose (Period-3), resulting in 2.2- to 3.3-fold higher exposure (Cmax and AUC) of DET. Rolapitant did not inhibit CYP2C9 following exposure to TOL. The exposure (Cmax & AUC) of CYP2C19 substrate OMP was minimally increased by rolapitant (1.1- to1.4-fold) and is unlikely to be clinically relevant. Rolapitant did not inhibit CYP2B6 or result in clinically relevant changes in exposure of EFA. Rolapitant did not inhibit CYP2C8 or result in clinically relevant changes in exposure of REP. There were no noteworthy adverse events or laboratory findings in any part of the study. Conclusions: Rolapitant was well-tolerated when co-administered with CYP probe substrates. Co-administration of rolapitant increased the exposure of DET. The inhibition of CYP2D6 can last at least 7 days following single dose of rolapitant. No clinically significant interaction was observed between rolapitant and substrates of CYP2C9, CYP2C19, CYP2B6 or CYP2C8; therefore no dosing adjustment is necessary for drugs which are metabolized by these CYPs. Citation Format: Xiaodong Wang, Zhi-Yi Zhang, Jing Wang, Sharon Lu, Sujata Arora, Lorraine Hughes, Jennifer Christensen, Vikram Kansra. Effects of rolapitant on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C62.

8063 Background: Both intrinsic and acquired resistance mechanisms to ALK inhibitors have been observed in ALK rearranged (ALK+) non-small cell lung cancer (NSCLC). TSR-011 inhibits ALK (IC50 = 0.7...

e19005 Background: Ultimately, the majority of anaplastic lymphoma kinase (ALK) rearranged (+) non-small cell lung cancers (NSCLC) are either unresponsive to crizotinib or develop resistance mutati...