ABSTRACT
BACKGROUND: Immunotherapy directed at 5T4 tumor antigen may delay the need for further chemotherapy. An attenuated modified vaccinia Ankara virus containing the gene encoding for 5T4 (MVA-5T4) was studied in asymptomatic relapsed ovarian cancer. OBJECTIVE: To assess the effectiveness and safety of MVA-5T4 as treatment for asymptomatic relapsed ovarian cancer. METHODS: TRIOC was a phase II randomized (1:1), placebo-controlled, double-blind multicenter study. The primary aim was to assess the effectiveness and safety of MVA-5T4 as a treatment for asymptomatic patients with relapsed ovarian cancer. Eligible patients had International Federation of Gynecology and Obstetrics (FIGO) stage IC1-III or IVA epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, Eastern Cooperative Oncology Group (ECOG) 0-1, with relapse defined by a rise in CA-125 to twice the upper limit of normal or low-volume disease on CT scan. The primary endpoint was disease progression (including deaths from ovarian cancer) at 25 weeks. Following a brief suspension, the trial restarted as a single-arm study. The revised single-arm design required 45 evaluable patients treated with MVA-5T4 to detect a 25-week progression rate of 50%, assuming an expected 70% rate without MVA-5T4; 85% power with one-sided 5% significance. RESULTS: A total of 94 eligible patients were recruited, median age was 65 years (range 42-82), median follow-up 34 months (range 2-46). Overall, 59 patients received MVA-5T4 and 35 patients received placebo. The median number of MVA-5T4 injections received was 7 (range 0-9), compared with a median of 6 (range 1-12) for patients receiving placebo. Median progression-free survival was the same in both arms (3.0 months). The 25-week progression rate was similar in both arms: 80.0% for patients treated with MVA-5T4 and 85.7% for those receiving placebo (risk difference -5.7%, 95% CI -21.4% to 10.0%). Median time to clinical intervention was improved with MVA-5T4: 7.6 months (range 6.7-9.5) vs 5.6 (range 4.9-7.6), CONCLUSION: MVA-5T4 vaccination in patients with asymptomatic relapse was well-tolerated but did not improve the progression rate at 25 weeks. The majority of patients who received MVA-5T4 had clinical intervention later than those assigned to placebo. TRIAL REGISTRATION NUMBER: NCT01556841.
ABSTRACT
Huntington's disease (HD) is an inherited progressive neurological disorder for which there is no effective therapy. It is caused by a CAG/polyglutamine repeat expansion that leads to abnormal protein aggregation and deposition in the brain. Several compounds have been shown to disrupt the aggregation process in vitro, including a number of benzothiazoles. To further explore the therapeutic potential of the benzothiazole aggregation inhibitors, we assessed PGL-135 and riluzole in hippocampal slice cultures derived from the R6/2 mouse, confirming their ability to inhibit aggregation with an EC50 of 40 microM in this system. Preliminary pharmacological work showed that PGL-135 was metabolically unstable, and therefore, we conducted a preclinical trial in the R6/2 mouse with riluzole. At the maximum tolerated dose, we achieved steady-state riluzole levels of 100 microM in brain. However, this was insufficient to inhibit aggregation in vivo and we found no improvement in the disease phenotype.
