Results of a phase IIb study in recurrent or refractory glioblastoma patients with the TGF-beta-2 inhibitor AP 12009

Abstract

12521 Background: The antisense phosphorothioate oligonucleotide compound AP 12009 targets TGF-beta2. Since TMZ is now used in the adjuvant setting in GBM there is a high need for new treatment options in recurrence. In three Phase I/II dose escalation trials with AP 12009 in high-grade glioma (HGG) patients complete and long lasting tumor responses had been observed. Methods: The study G004 is an international open-label, randomized, active controlled, dose-finding Phase IIb study. Objective is a comparison of two doses of AP 12009 and standard chemotherapy. A total of 145 patients with histopathologically confirmed recurrent or refractory HGG (WHO Grades III and IV) were randomized into three treatment arms. Patients received treatment with low dose AP 12009 (10 μM), high dose AP 12009 (80 μMM), or standard chemotherapy TMZ or PCV. AP 12009 was applied by convection-enhanced delivery during using 7-day-on, 7-day-off cycles. Maximum number of cycles was 11. Results: Here we report on patients with recurrent or refractory glioblastoma (GBM, WHO Grade IV; AA patients see separate abstract). Out of 95 GBM patients treated, 28 pts received 10 μM AP 12009, 34 pts AP 12009 80 μM, and 33 pts standard chemotherapy (28 TMZ, 5 PCV). Median age differed between treatment groups (see table ). Dose finding was achieved, as efficacy and safety results for the AP-10 group were superior to those of the AP-80 group (see table ). Comparable hazard ratios for survival were seen in the three treatment groups (see table ). Long lasting responses were observed in both AP 12009 groups. Conclusions: The safety profile of AP 12009 in GBM patients was good. The durable responses in both AP 12009 groups and the survival data confirm the proof of concept obtained in Phase I/II trials for treatment of recurrent GBM patients with AP 12009. [Table: see text] No significant financial relationships to disclose.