This registry represents the longest and largest naturalistic study of efficacy outcomes in treatment-resistant depression, and it provides additional evidence that adjunctive VNS has enhanced antidepressant effects compared with treatment as usual in this severely ill patient population.

Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors. Patients and Methods: Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modified Fibonacci scheme ranging from 3.9 to 45.7 mg/m 2 . Pharmacokinetic samples were collected during the first course. Results: Neutropenia was the principal DLT at the 45.7 mg/m 2 /d dose level. In addition, one patient also experienced grade 3 neutropenia complicated with grade 3 esophageal candidiasis and grade 3 dehydration. Only 1 of 11 patients treated at the MTD, 34.4 mg/m 2 , experienced dose-limiting neutropenia. Other common, drug-related toxicities included mild to moderate fatigue, anemia, nausea, anorexia, emesis, alopecia, and diarrhea. The best observed antitumor response consisted of stable disease and was noted in 10 patients (31%); the median duration on study for those patients with stable disease was 99.5 days compared with 37.5 days for those patients with progressive disease. Tasidotin plasma concentrations declined biphasically with an effective half-life of V55 minutes, and f11% was excreted unchanged in the urine. Conclusion: The recommended dose for phase II studies and the MTD when tasidotin is administered on days 1, 3, and 5 every 3 weeks is 34.4 mg/m 2 . The favorable toxicity profile of tasidotin compared with other antitubulin agents, including other dolastatin analogues, and its novel mechanism of action support further disease-directed evaluation of this agent.

In many multicenter clinical trials, the total sample size (N), the power (1-β), and the significance level (α) are decided at the time of trial design and protocol development. Although it may be recognized that equal center enrollment is the ideal, it is not practical and rational to limit enrollment per center in order to attain an equal number of subjects per center. Extreme unequal center enrollments may occur, which may lead to loss of power and loss of sensitivity to detect the treatment difference. In this manuscript, a method of computing a coefficient of imbalance (Λ) is introduced as a tool to utilize in assessing power loss in relation to unequal center sizes. This strategy is particularly useful for statistical analyses utilizing unweighted (Type III) analysis methods viewed to be most affected by extreme center imbalances in hypothesis testing and parameter estimates. Numerical examples illustrating the utility of Λ in deriving effective sample size (Ne) and adjusted power (1-βA) for center imbalances are provided utilizing published data. The advantage is that Λ, Ne, and 1-βA can be computed any time while a study is ongoing for decision purposes, even for blinded studies, since the computations do not require breaking the blind.

Metastatic melanoma continues to be a very difficult disease to treat. Options are limited and often have very little impact on the course of the disease. The objective of the current study was to evaluate the efficacy and safety of continuously administered Apomine (SR-45023A), a novel bisphosphonate, in patients with previously treated metastatic malignant melanoma. Adult patients with previously treated metastatic melanoma received Apomine 100 mg orally, twice daily (total dose 200 mg per day) continuously for 28 days (defined as a cycle). Treatment was continued until disease progression or unacceptable toxicity. A total of 42 patients received at least one dose of Apomine. Stable disease was achieved in 2 patients (5%). No complete or partial responses were observed. Progression free survival of at least 16 weeks was observed in 6 patients (14%). The median overall survival was 6.1 months (95% CI, 4.9-9.4 months). Time to treatment failure was 1.7 months (95% CI, 1.6-1.8 months) with Apomine therapy. By cycle 2, Apomine concentrations reached steady-state. Apomine was well tolerated with only 37% of patients experiencing any drug-related event. Abdominal pain was the most frequent adverse event occurring in 26% of patients. In conclusion, Apomine, at the current dose studied, failed to produce a 30% progression free survival rate at 16 weeks considered to be a meaningful benefit for further development.

No abstract

No abstract

No abstract