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Background This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. Clinical trial registration ClinicalTrials.gov, NCT01058707.

Background: The proteasome inhibitor bortezomib undergoes oxidative biotransformation via multiple cytochrome P450 (CYP) enzymes, with CYP3A4 identified as a partial, yet potentially important, contributor based on in vitro drug metabolism studies. Objective: The aim of this study was to assess the effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib. Methods: This was a prospective, multicenter, openlabel, randomized, multiple-dose, 2-way crossover study in patients with advanced solid tumors. All patients received bortezomib 1.0 mg/m 2 IV (on days 1, 4, 8, and 11 of two 21-day cycles) and were randomized to receive concomitant ketoconazole 400 mg on days 6, 7, 8, and 9 of cycle 1 or 2. Serial blood samples were collected over the day-8 dosing interval (immediately prior to bortezomib administration, and from 5 minutes to 72 hours after administration) in cycles 1 and 2 for measurement of plasma bortezomib concentrations for noncompartmental PK analysis and blood 20S proteasome inhibition for PD analysis. All adverse events (AEs) were recorded during each cycle including serious AEs and all neurotoxicity events for up to 30 days after the last dose of bortezomib. Results: Twenty-one patients (median age, 57 years; sex, 67% male; race, 86% white; median body surface area, 2.01 m 2) were randomized to treatment. Twelve pa- tients completed the protocol-specified dosing and PK sampling in both cycles 1 and 2. Assessment of the effect of ketoconazole on bortezomib PK and PD was based on data in these 12 PK-evaluable patients. The ratio of geometric mean bortezomib AUC 0-tlast(AUC from time 0 to last quantifiable concentration) for bortezomib plus ketoconazole versus bortezomib alone was 1.352 (90% CI, 1.032–1.772). Consistent with this observed mean increase in bortezomib exposure, concomitant administration of ketoconazole was associated with a corresponding increase (24%–46%) in the blood proteasome inhibitory effect. Conclusion: Concomitant administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a mean increase of 35% in bortezomib exposure. ClinicalTrials.gov identifier: NCT00129207.

Abstract Study Objectives Idiopathic hypersomnia (IH) is a chronic disorder characterized by excessive daytime sleepiness unexplained by another disorder or drug/medication use. Although the orexin system plays a role in sleep-wake regulation, orexin A levels in the cerebrospinal fluid are normal in people with IH. This phase 1b, randomized, placebo-controlled, crossover study aimed to investigate the safety, pharmacokinetics, and pharmacodynamics of danavorexton, a small-molecule orexin-2 receptor agonist, in adults with IH. Methods Adults with IH aged 18–75 years were randomized to one of two treatment sequences of single intravenous infusions of danavorexton 112 mg and placebo. Pharmacodynamic endpoints included the maintenance of wakefulness test (MWT), the Karolinska Sleepiness Scale (KSS), and the psychomotor vigilance task (PVT). Adverse events were monitored throughout the study period. Results Of 28 randomized participants, 12 (44.4%) had a treatment-emergent adverse event (TEAE) and 10 (37.0%) had a TEAE considered related to study drug, most of which were mild or moderate. Four participants (18.2%) had urinary TEAEs while receiving danavorexton, all of which were mild in severity. There were no deaths or TEAEs leading to discontinuation. Improvements in MWT, KSS, and PVT scores were observed with danavorexton compared to placebo. Following drug administration, a mean sleep latency of 40 min (maximum value) was observed during the MWT within 2 h of danavorexton infusion in most participants. Conclusions A single infusion of danavorexton improves subjective and objective excessive daytime sleepiness in people with IH with no serious TEAEs, indicating orexin-2 receptor agonists are promising treatments for IH. Clinical Trial: Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT04091438 Graphical Abstract Graphical Abstract

In this phase 2 randomized, placebo-controlled trial involving 112 participants with narcolepsy type 1, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over a period of 8 weeks.

Summary Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1–21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2–22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median T max was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2–22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46–97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned.

Purpose Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses. Methods Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m², days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected. Results Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102-112 L/h for first dose; 15-32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m² group. Conclusions Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m² doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.

Purpose To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population. Patients and Methods Sixty-two adult cancer patients received intravenous bortezomib at 0.7–1.5 mg/m 2 on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m 2 into five cohorts: normal renal function (≥60 ml/min/1.73 m 2 ); mild dysfunction (40–59 ml/min/1.73 m 2 ); moderate dysfunction (20–39 ml/min/1.73 m 2 ); severe dysfunction (<20 ml/min/1.73 m 2 ); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed. Results Bortezomib escalation to the standard 1.3 mg/m 2 dose was well tolerated in all patients with CrCl ≥20 ml/min/1.73 m 2 ; 0.7 mg/m 2 was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m 2 ). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m 2 in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function. Conclusion Bortezomib 1.3 mg/m 2 is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.

To determine the maximum tolerated dose (MTD), the incidence and severity of toxicities, and the pharmacokinetics of lobradimil administered intravenously over 10 min in combination with carboplatin in children with refractory brain tumors. A group of 25 children with primary brain tumors received carboplatin and lobradimil on two consecutive days every 28 days. The 10-min lobradimil infusion began 5 min before the end of the carboplatin infusion. Four lobradimil dose levels (100, 300, 450 and 600 ng/kg ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carboplatin was adaptively dosed based on the glomerular filtration rate to achieve a target plasma area under the concentration-time curve (AUC) of 7.0 mg min/ml per course (5.0 mg min/ml for patients who had previously received craniospinal radiation or myeloablative chemotherapy). Lobradimil toxicity was immediate, tolerable and rapidly reversible. The most frequent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during the lobradimil infusion. The incidence and severity of lobradimil toxicities were not dose-related and the lobradimil dose was not escalated beyond the 600 ng/kg IBW dose level. Two patients had partial responses and ten patients had stable disease. Myelosuppression (thrombocytopenia more prominent than neutropenia) was the primary toxicity attributed to carboplatin. Lobradimil pharmacokinetics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability. The combination of carboplatin and lobradimil is safe and tolerable. An MTD for lobradimil was not defined because toxicity was not dose-related. The recommended pediatric phase II dose of lobradimil is 600 ng/kg IBW.

Major federal legislative changes were made during the 1980s and early 1990s in an attempt to improve healthy birth outcomes by amending Title XIX of the Social Security Act. These actions liberalized financial criteria used to determine eligibility for Medicaid-covered prenatal care so that a wider array of women could briefly access government-financed health care until the end of two months post partum. The purpose of this study was to identify, describe, and evaluate local, state, and federal efforts to implement these eligibility expansions, as well as to provide stakeholders with timely feedback so they could mediate any identified barriers. At the time of this study, little data were available, the population was relatively unknown, and the policy changes were at the implementation stage; therefore, the tenets of a normative implementation environment evaluation were integrated with fourth generation methodology (the hermeneutic dialectic within-circle process) to conduct this study. Stakeholders at the local, state, and federal levels were interviewed either on-site or via telephone to elicit multiple perspectives of the implementation process. Findings showed that access to prenatal care for low-income pregnant women is a complex problem. A unidimensional, quick legislative fix to remove financial eligibility barriers is only a beginning step in efforts to attenuate disparities in accessing pregnancy-related medical assistance. Internal dynamics of implementation--communication issues (outreach, policy guidance, and data collection/reporting) and infrastructure issues (administration, application process and service delivery)--also need to be addressed at all levels (local, state, and federal). These findings reinforce the need for continual readjustments to policies affecting access to, and delivery of, Medicaid-covered prenatal care before the intended goal of increasing healthy birth outcomes is actualized. State and federal recommendations were formulated to address such concerns.