Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study).

PURPOSE: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial. PATIENTS AND METHODS: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses. RESULTS: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9-5.3), 5.4 (4.2-6.4), and 4.6 (4.2-5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84-1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred. CONCLUSIONS: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262)See related commentary by Salas-Benito et al., p. 5435.

Steady-state bioavailability of prescription omega-3 on a low-fat diet is significantly improved with a free fatty acid formulation compared with an ethyl ester formulation: the ECLIPSE II study.

The systemic bioavailability of free fatty acid (FFA) forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with ethyl ester (EE) forms is dependent on the presence of intestinal lipases and is highest during consumption of high-fat meals. Given that patients with cardiovascular disease are advised to reduce dietary fat intake, potentially lowering the bioavailability and therapeutic benefit, the hypothesis that FFA forms provide for higher bioavailability compared with EE forms under low-fat diet conditions was tested where the pharmacokinetics of the FFA form (Epanova™) were compared with those of an ethyl ester form (Lovaza®) following repeat dosing. Fifty-two healthy male and female subjects were equally allocated to one of two open-label, parallel-group cohorts. Following a Therapeutic Lifestyle Changes diet for a minimum of 7 days, blood samples were drawn for endogenous values for EPA and DHA over a 24-hour period. Subjects were then administered 4 × 1 g capsules of either Epanova (OM3 FFA) or Lovaza (OM3 EE) once daily for 14 days, following which serial blood samples were drawn over a 24-hour period to characterize the bioavailability of EPA and DHA from the respective formulations. In addition, changes from baseline in lipid profile were explored. Systemic bioavailability, as measured by area under the curve from time zero to 24 hours (AUC(0-τ)) and the maximum measured plasma concentrations during the 0-24 hour dosing interval (C(max,ss)) of unadjusted total plasma EPA + DHA were approximately 3-fold and 3.9-fold higher, respectively, for Epanova relative to Lovaza. Following baseline adjustment, the magnitude of difference in bioavailability was approximately 5.8-fold and 6.5-fold higher in AUC(0-τ) and C(max,ss), respectively, for Epanova relative to Lovaza. Serum triglycerides were reduced by a significantly greater extent (P = 0.013) for Epanova relative to Lovaza (21% versus 8%). The bioavailability of the FFA forms of EPA and DHA in Epanova are significantly greater than the bioavailability from the EE forms present in Lovaza under low-fat dietary conditions normally recommended for patients with cardiovascular disease. This increased bioavailability may lead to improved triglyceride-lowering in patients with hypertriglyceridemia.

Effect of dose on the frequency of major birth defects following fetal exposure to lamotrigine monotherapy in an international observational study.

Data from the International Lamotrigine Pregnancy Registry were analyzed to examine the effect of maximal first-trimester maternal dose of lamotrigine monotherapy on the risk of major birth defects (MBDs). Among 802 exposures, the frequency of MBDs was 2.7% (95% confidence interval [CI] 1.8-4.2%). The distribution of dose did not differ between infants with and those without MBDs (mean 248.3 milligrams per day [mg/day] and 278.9 mg/day, respectively, median 200 mg/day for both groups). A logistic regression analysis showed no difference in the risk of MBDs as a continuous function of dose (summary odds ratio [OR] per 100 mg increase =0.999, 95% CI 0.996-1.001). There was also no effect of dose, up to 400 mg/day, on the frequency of MBDs.

A phase II study of depsipeptide in refractory metastatic renal cell cancer.

BACKGROUND: Therapeutic options for renal cell cancer are inadequate. Depsipeptide is a histone deacetylase inhibitor with promising preclinical and early clinical activity. PATIENTS AND METHODS: Patients with refractory renal cell cancer with normal organ function and no history of significant cardiovascular disease were enrolled on a multi-institutional, single-arm, phase II study. Patients received depsipeptide 13 mg/m2 intravenously over 4 hours on days 1, 8, and 15 of a 28-day cycle with disease reevaluation performed every 8 weeks. One response in the initial 16 enrolled patients was required for full accrual to 25 patients, from which 5 responses needed to be observed in order to consider the agent appropriate for further study. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria, version 2.0. RESULTS: The 29 evaluable patients, who were accrued so that 25 patients who received >or= 3 doses of depsipeptide could be observed, were heavily pretreated with a median of 2 previous systemic therapies and a 2-year median duration of metastatic disease. Twenty-four had clear-cell histology. The most common serious toxicities were fatigue, nausea, vomiting, and anemia. Two patients developed a prolonged QTc interval, one patient each developed grade 3 atrial fibrillation and tachycardia, and there was 1 sudden death. Two patients experienced an objective response (1 complete response) for an overall response rate of 7% (95% CI, 0.8%-23%). CONCLUSION: Depsipeptide at this dose and schedule does not have sufficient activity for further investigation in this patient population.