Abstract 3716: Targeted therapy of high-grade gliomas using TGF-beta2 inhibitor trabedersen (AP 12009): Results of the Phase IIb study as basis for the Phase III SAPPHIRE Study

Abstract

Abstract Background: High-grade gliomas (HGG) strongly overexpress TGF-beta 2. Trabedersen, a phosphorothioate antisense oligonucleotide is a TGF-beta 2 inhibitor administrated intratumorally using convection-enhanced delivery (CED). So far, clinical studies in HGG have included three Phase I/II studies and one randomized, active-controlled, open-label, multinational dose-finding Phase IIb study. Methods: Main objectives of the Phase IIb study were to compare response rate, survival, and safety of 2 doses of trabedersen (10 µM or 80 µM) vs. standard chemotherapy (TMZ or PCV). 145 patients with recurrent or refractory HGG (AA WHO grade III or GBM WHO grade IV) were randomized. Trabedersen was given intratumorally by convection-enhanced delivery via a single multi-hole catheter with up to 11 treatment cycles (7-d-on, 7-d-off / cycle). Results: As in the previous Phase I/II studies, treatment with trabedersen led to long-lasting remissions in patients with recurrent or refractory AA or GBM. Trabedersen showed a good tolerability and safety profile. Overall, 10 µM was superior to 80 µM trabedersen in both efficacy and safety. Overall, the highest efficacy was observed in AA patients treated with the lower dose of trabedersen. The 10 µM trabedersen group showed a consistently higher survival rate compared to 80 µM trabedersen and standard chemotherapy (at 24 months: 83.3%, 53.3% and 41.7%, respectively). Duration of response was about 3 times longer in the 10 µM trabedersen group (29.1 months) compared to the standard chemotherapy group (8.0 months). The median overall survival was higher in both trabedersen groups than in the chemotherapy control group, with a remarkable survival benefit of 10 µM trabedersen over chemotherapy of 17.4 months. In GBM patients, trabedersen was as efficacious as standard chemotherapy. Furthermore, in a prespecified subgroup (age ≤55 years, KPS >80%), trabedersen patients had a markedly higher 2-year survival rate compared to standard chemotherapy (40.0 vs. 13.3%). Conclusion and Outlook: Trabedersen treatment is safe and has a clear clinical benefit in HGG. A randomized, multinational and active-controlled Phase III study (SAPPHIRE) with trabedersen as monotherapy in patients with recurrent or refractory AA (WHO grade III) has started and patient enrollment is ongoing. In this pivotal study, patients are randomized either to treatment with 10 µM trabedersen or to standard chemotherapy (TMZ or BCNU). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3716.