Therapeutically-induced stable disease in oncology early clinical trials.

RATIONALE:The RECIST guideline defines four categories of response to treatment for cancer patients according to post-baseline changes in tumor burden, hence ignoring disease history. However, if left untreated, tumors grow exponentially, implying that pretreatment changes in tumor size are key to thoroughly assess efficacy. We present a model-based approach to estimate the rates of changes in tumor mass, before and after treatment onset. METHODS:Sixty-eight patients were eligible for the analysis of tumor size data from a Phase 1 study evaluating the effect of emactuzumab. In addition to tumor size measured at baseline and every six weeks during treatment, a pre-baseline measurement was gathered for each patient. A longitudinal regression model was used to estimate the rates of tumor size change before and after treatment onset. RESULTS:The median pre-treatment tumor growth exponential rate was equal to 0.022 month-1, corresponding to a tumor size doubling time of 4 months, and the on-treatment median tumor shrinkage exponential rate was equal to 0.001 month-1. Among sixteen patients categorized as stable disease per RECIST, only five had similar slopes before and after treatment while nine actually improved. One patient in particular had a therapeutically induced stabilization of the disease. CONCLUSION:Our analysis emphasizes the importance of collecting pre-baseline scans to distinguish therapeutically induced stable disease from cases where the tumor growth is not perturbed by treatment

No clinically relevant drug–drug interactions when dalcetrapib is co-administered with atorvastatin

Dalcetrapib, a cholesteryl ester transfer protein modulator, under development to increase high-density lipoprotein cholesterol and potentially decrease cardiovascular risk, will potentially be co-prescribed to women on oral contraceptive (OC). Objective: Assess the effect of dalcetrapib on the pharmacokinetics and ability to suppress ovulation of Microgynon® 30, a representative monophasic OC. Materials and methods: A single-center, randomized, open-label, two-period crossover study in healthy women receiving monophasic OC. Subjects received Microgynon® 30 (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) once daily for 21 days followed by 7 treatment-free days (run-in period), then were randomized to Microgynon® 30 daily for 21 days with or without dalcetrapib 900 mg daily for Day 1 - 14. Plasma ethinylestradiol and levonorgestrel were measured on Day 14, and luteinizing hormone, follicle stimulating hormone, progesterone and estrogen from Day 11 - 14. The primary endpoint plasma exposure (AUC 0-24and C max) on Day 14 was evaluated for ethinylestradiol and levonorgestrel. Safety was monitored throughout. Results: 30 subjects were randomized. The exposure of ethinylestradiol and levonorgestrel was similar when Microgynon® 30 was administered with or without dalcetrapib; for ethinylestradiol the geometric mean ratio %, (90% confidence interval (CI)) for AUC0-24 and C max were 92 (86 - 98) and 105 (95 - 115) and for levonorgestrel 92 (88 - 96) and 93 (87 - 99), respectively. Concentrations of luteinizing hormone, follicle stimulating hormone, estrogen and progesterone were comparable between treatments. Conclusions: Dalcetrapib has no clinically relevant effect on the pharmacokinetics of ethinylestradiol and levonorgestrel. Contraceptive efficacy of Microgynon® 30 is not anticipated to be compromised by co-administration of dalcetrapib. ©2012 Dustri-Verlag Dr. K. Feistle

Effects of high-density lipoprotein elevation with cholesteryl ester transfer protein inhibition on insulin secretion

RATIONALE:: High-density lipoprotein cholesterol elevation via cholesteryl ester transfer protein (CETP) inhibition represents a novel therapy for atherosclerosis, which also may have relevance for type 2 diabetes mellitus. OBJECTIVE:: The current study assessed the effects of a CETP inhibitor on postprandial insulin, ex vivo insulin secretion, and cholesterol efflux from pancreatic β-cells. METHODS AND RESULTS:: Healthy participants received a daily dose of CETP inhibitor (n=10) or placebo (n=15) for 14 days in a randomized double-blind study. Insulin secretion and cholesterol efflux from MIN6N8 β-cells were determined after incubation with treated plasma. CETP inhibition increased plasma high-density lipoprotein cholesterol, apolipoprotein AI, and postprandial insulin. MIN6N8 β-cells incubated with plasma from CETP inhibitor-treated individuals (compared with placebo) exhibited an increase in both glucose-stimulated insulin secretion and cholesterol efflux over the 14-day treatment period. CONCLUSIONS:: CETP inhibition increased postprandial insulin and promoted ex vivo β-cell glucose-stimulated insulin secretion, potentially via enhanced β-cell cholesterol efflux