The management of patients with glioblastoma remains challenging with an average survival of 32-56 weeks. We report on a clinical trial of patients with recurrent glioblastoma treated with adenovirus/herpex simplex-thymidine kinase/ganciclovir (ADV/HSV-tk/GC). Entry criteria for this study included: recurrent malignant glioma after surgical resection and conventional radiation therapy. At the time of recurrence, computerized volumetric resection of the tumor was performed and the ADV/HSV-tk complex was injected in the tumor bed. GC was administered 24 h after surgery (10 mg/kg/day) for 7 days. Patients were divided into 3 ADV/HSV-tk dose-escalating cohorts. Adenoviral vector shedding, and local or systemic toxicity did not occur in this study. Magnetic resonance imaging showed lack of increased brain edema in the treated patients. Histological examination of the 5 patients that had repeated surgery after gene therapy treatment showed lack of tissue toxicity. Additionally, PCR for HSV-tk was negative in the brain 3 months after injection. The patients' Karnofsky score was maintained > or = 70 in 8/10 patients (80%) and 5/9 patients (55%) 3 and 6 months respectively, after gene therapy. Ten of 11 patients survived > or = 52 weeks from diagnosis with an average survival of 112.3 weeks. One patient is still alive 248 weeks from diagnosis. These data show that the ADV/HSV-tk/GC complex at the dose used in this study is safe. Additional dose escalation is currently in progress.

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Introduction: Anacetrapib, a cholesteryl ester transfer protein inhibitor, has been shown to robustly reduce atherogenic lipoproteins including low-density lipoprotein cholesterol (LDL-C), Apo B and raise high-density lipoprotein cholesterol (HDL-C) as well as ApoA1. Hypothesis: This 1-year, Phase 3, multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy and safety profile of anacetrapib added to optimized LDL-C lowering therapy in patients with heterozygous familial hypercholesterolemia (HeFH). Methods: Patients with a genotype-confirmed or clinical diagnosis of HeFH, treated with an optimal dose of statin ± other lipid-modifying medication(s) and having an LDL-C ≥100 mg/dL without history of cardiovascular disease or LDL-C ≥70 mg/dL with a history of CVD were randomized in a ratio of 2:1 to anacetrapib 100 mg (n=204) or placebo (n=102) for 52 weeks followed by a 12-week reversal phase. The primary end points were the percent change from baseline in LDL-C (beta-quantification method) and the safety profile of anacetrapib. This trial is registered in ClinicalTrials.gov, #NCT01524289. Results: A total of 306 patients were enrolled at 25 sites in 9 countries. At baseline, most patients were on high-dose statin therapy and >70% also were on ezetimibe. Baseline LDL-C and HDL-C were 129.4 and 53.3 mg/dL, respectively. At Week 52, anacetrapib vs. placebo significantly reduced LDL-C by 39.7% and increased HDL-C by 102.1% (p<0.001 for both). Significant placebo-adjusted reductions in Apo B (24.8%) and increases in Apo A-I (32.9%) also were observed. Significantly more patients in the anacetrapib vs. placebo group achieved LDL-C <100 (82% vs. 18%; p<0.001) and <70 mg/dL (44% vs. 5%; p<0.001). Sustained effects on LDL-C (21.9%; p<0.001) and HDL-C (53.0%; p<0.001) were seen 12-weeks after cessation of anacetrapib therapy. No clinically important between-group differences were seen in the proportions of patients with abnormalities in liver enzymes, CK, blood pressure, electrolytes, adverse experiences and adjudicated CV events. Conclusion: In patients with HeFH, treatment with anacetrapib for 1 year was generally well tolerated and resulted in substantial reductions in LDL-C and increases in HDL-C.