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Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70-110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54·1% and 73·1% of patients derived clinical benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts, respectively. Progression-free survival ranged from 1·8 to 22·8 months and 11·8 to 26·3 months in responders with DLBCL and FL, respectively. The most frequent treatment-related adverse events were fatigue (75·0%), nausea (69·4%) and diarrhoea (61·1%). Although mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clinical benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.

Tesamorelin, a synthetic growth hormone-releasing hormone, is indicated for the reduction of visceral adipose tissue (VAT) in people with HIV. Here, we performed a post hoc analysis of participants receiving tesamorelin for 26 weeks in a phase III clinical trial. Efficacy data were compared between individuals with and without dorsocervical fat, stratified by tesamorelin response. Among tesamorelin responders, VAT and waist circumference (WC) decreased in both dorsocervical fat groups and did not statistically differ (VAT P = 0.657, WC P = 0.093). These data demonstrate that tesamorelin is equally effective and should be considered in the treatment of excess VAT regardless of the presence of dorsocervical fat. [ABSTRACT FROM AUTHOR]

The various metabolic effects of a growth hormone-releasing factor analogue, tesamorelin in HIV patients are discussed. Results reveal that tesamorelin helps in decreasing the visceral fat accumulation in the patients.

A novel transdermal formulation of fentanyl-containing dipropylene glycol droplets dispersed in a silicone matrix with a rate-controlling membrane was developed. Healthy male subjects (n = 24) received repeated 72-hour applications [...]

Lovastatin appears to reduce cholesterol levels in boys with familial hypercholesterolemia (FH), but levels in most still remained higher than normal. FH is a genetically inherited defect that causes high cholesterol levels. Persons carrying the gene are at high risk for heart disease. Researchers randomly assigned 69 boys with FH aged 17 or younger to 8 weeks of oral lovastatin at one of four dosages. Prior to taking the actual drug, all 69 boys took a placebo pill for 4 weeks. Cholesterol levels were unchanged during the period taking the placebo. Depending on the dosage, total cholesterol levels dropped by 17% to 29% and levels of low-density lipoprotein cholesterol (LDL), the so-called "bad cholesterol," dropped by 21% to 36%. Nonetheless, nearly two-thirds of the group continued to have total cholesterol and LDL cholesterol values beyond the normal range. Lovastatin caused no adverse effects serious enough to cause withdrawal from the study., Objective. Familial hypercholesterolemia (FH), an inherited autosomal dominant disorder of lipoprotein metabolism, is associated with premature atherosclerosis. The recommended pediatric therapy consists of dietary intervention and, when necessary, treatment with bile acid-binding resins. However, compliance has been poor in many children. Therefore, our objectives were to determine the efficacy, safety, and tolerance of the short-term use of lovastatin, a 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitor, in the control of severe FH in a male pediatric population and to evaluate the dose-response relationship. Methods. Sixty-nine male patients with FH 12.9 [+ or -] 2.4 years of age (mean [+ or -] SD) participated in this multicenter, randomized, double-blind trial. After a 4-week placebo period, the patients were, allocated to four treatment groups (lovastatin 10, 20, 30, or 40 mg/d) for 8 weeks. Plasma lipid and apolipoprotein (Apo) concentrations were measured every 2 weeks. Clinical and laboratory evidence of adverse events was monitored periodically throughout the study. Results. All lovastatin doses reduced total cholesterol (-17% to 29%), low-density lipoprotein cholesterol (-21% to 36%), and ApoB (-19% to -28%) concentrations. A dose-response relationship was seen, and between-group comparisons showed that results were significantly improved up to a dose of 30 mg/d. We observed a 7% increase in high-density lipoprotein cholesterol and a 4% increase in ApoA1 concentrations. The medication was well tolerated by all patients. No serious clinical adverse experience was reported. Lovastatin increased aspartate aminotransferase concentrations, but there was no evidence of a dose-response relationship, and no value exceeded two times the upper limit of normal. No significant change in alanine aminotransferase was observed. Three patients had marked (more than three times the upper limit of normal) asymptomatic elevations in their creatine kinase values, which returned spontaneously to normal, and no action was required regarding the drug. Conclusions. Lovastatin is an effective therapy for severe FH in children and adolescents. It was well tolerated, and the occurrence of adverse experiences of clinical significance was very low. Long-term pediatric studies are indicated. Pediatrics 1996,97-619-628; familial hypercholesterolemia, children, adolescent, drug therapy, lovastatin., ABBREVIATIONS. LDL, low-density lipoprotein; FH, familial hypercholesterolemia; HDL, high-density lipoprotein; Apo, apolipoprotein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CK, creatine kinase. Coronary heart disease caused by atherosclerosis is an important [...]

Background: The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study.Methods: Eligible patients with platinum-treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28-day cycles in a 3-stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.Results: Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent-to-treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose-normalized maximum serum concentration [Cmax ] after TIW dosing of 0.2 ng/mL/mg).Conclusions: To the authors' knowledge, the current study represents the first clinical trial using genomic-based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and efficacy of mocetinostat (a Class I/IV HDAC inhibitor) in combination with gemcitabine in patients with solid tumors, including pancreatic cancer.Methods: In this open-label, non-randomized Phase I/II study (NCT00372437) sequential cohorts of patients with solid tumors received gemcitabine (1000 mg/m2, day 1 of three consecutive weeks, 4-week cycles) and oral mocetinostat [50-110 mg, three times per week (TIW)]. The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) was determined based on dose-limiting toxicities in Cycle 1 (Phase I study). The MTD/RP2D was further evaluated in patients with advanced pancreatic cancer (Phase II study) using a two-stage design. The Phase II primary endpoint was overall response rate (ORR).Results: Forty-eight patients were enrolled into the Phase I (n = 25) and Phase II (n = 23) studies. In the Phase I study, the MTD/RP2D was mocetinostat 90 mg TIW + gemcitabine 1000 mg/m2. Grade ≥ 3 treatment-related adverse events (AEs) were reported by 81% of all patients, the most frequent being fatigue (38%) and thrombocytopenia (19%). The ORR was 11% in the Phase I study (n = 2 patients with pancreatic cancer, responses lasting for 16.8 and 4.0 months, respectively). As no responses were seen in the Phase II cohort, the study was terminated.Conclusions: Mocetinostat TIW in combination with gemcitabine was associated with significant toxicities in patients with advanced pancreatic cancer. The level of clinical activity of this treatment combination was not considered high enough to merit further testing in this setting. [ABSTRACT FROM AUTHOR]

The article offers information on optimization of clinical end- point bioequivalence (CEBE) studies for the new drug application submissions in U.S. Topics discussed include CEBE studies are commonly used to demonstrate bioequivalence between prospective generic and reference product formulations; importance of new drug trials in patient enrichment strategies; and replication strategy for controlling sample size.

In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70-143% within each of two ranges of intra-subject coefficient of variation (10-30% and 30-55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at [ABSTRACT FROM AUTHOR]