A phase IIb actively controlled study with the TGF-beta-2 inhibitor AP 12009 for recurrent or refractory anaplastic astrocytoma

Abstract

2025 Background: The TGF-β2 antisense phosphorothioate oligonucleotide inhibitor AP 12009 is a targeted anti-tumor therapy for TGF-β2 overexpressing tumors. In three Phase I/II dose escalation studies complete and long-lasting responses were observed in patients with recurrent or refractory anaplastic astrocytoma. Methods: The Phase IIb actively controlled dose finding study G004 is an open-label, randomized trial in adult patients with recurrent or refractory high-grade glioma (HGG) confirmed by central histopathology. 145 patients were randomized into three groups: Low dose AP 12009 (10 μM), high dose AP 12009 (80 μM), or standard chemotherapy, i.e. TMZ (or PCV if TMZ had already failed). Study objective was to compare the efficacy and safety of the three treatment groups. AP 12009 was applied locoregionally by convection- enhanced delivery (CED) with up to 11 treatment cycles (7-day-on, 7-day-off / per cycle). Results: Here we report on patients with recurrent anaplastic astrocytoma (AA, Grade III; GBM patients see separate abstract). 39 AA patients were treated, 12 pts received AP 12009 10 μM (AP-10), 15 pts 80 μM (AP-80), and 12 pts standard chemotherapy (10 pts TMZ, 2 pts PCV). Preliminary safety data reveal no SAEs related to the study drug in the AP-10 and AP-80 groups vs. one in the control group. Survival rates were higher in both AP 12009 groups compared to the chemotherapy group (see table ). In both AP 12009 groups mOS has not yet been reached. Overall survival at present is 28.6 months for the AP-10 group, 24.2 months for the AP-80 group, and 20.2 months for the control group. 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 ). Conclusion: AP 12009 revealed a positive benefit-risk profile and demonstrated excellent potential as monotherapy for the treatment of recurrent or refractory AA patients, especially for the AP 12009 10 μM group. [Table: see text] [Table: see text]