Randomized, active-controlled phase IIb study with trabedersen (AP 12009) in recurrent or refractory high-grade glioma patients: Basis for phase III endpoints

2037 Background: High-grade gliomas (HGG) strongly overexpress TGF-beta 2. Trabedersen (AP 12009), a TGF-beta 2-specific inhibitor, was successfully tested in 3 Phase I/II studies in recurrent or refractory HGG. Methods: The Phase IIb study AP 12009-G004 was an open-label, randomized, active-controlled dose-finding study. Main objectives: 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 and 134 patients (AA = 39; GBM = 95) received study medication. Trabedersen was given intratumorally by convection-enhanced delivery. Results: AA and GBM patients in both trabedersen groups had long-lasting tumor responses (currently up to 4 years). AA: (10 μM trabedersen vs. control): significantly better overall response rate was noted at 14 months (CR+PR; p=0.034*) and lower tumor progression rates at 6, 12 and 14 months; difference at 14 months was statistically significant (p=0.003*). 2-year survival rate was 2-fold higher (p=0.088**). Tumor progression rate at 14 months and 2-year survival rate correlated with a median overall survival benefit of 17.4 months. GBM: 10 μM trabedersen was as efficacious as standard chemotherapy in all patients. It was clearly superior regarding 2-year survival in the pre-specified subgroup of patients younger than 55 years and the subgroup with a KPS > 80. The superior long-term survival of trabedersen-treated AA and GBM patients was the basis for extending the follow-up period of this Phase IIb study. Conclusions: Based on Phase IIb results, the pivotal Phase III study SAPPHIRE in recurrent or refractory AA patients has started. Primary efficacy endpoint is 2-year survival rate; secondary endpoints are progression rate at 14 months, time to death, quality of life, safety and tolerability. A separate study in GBM is being planned. [Table: see text] [Table: see text]