Targeted therapy for high-grade glioma with the TGF-beta 2 inhibitor trabedersen: results of a randomized and controlled phase IIb study

This randomized, open-label, active-controlled, dose-finding phase fib study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 mu M or standard chemotherapy (temozolomide or procarbazine/lomustine/ vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 mu M trabedersen vs chemotherapy (p=.0032). The 2-year survival rate had a trend for superiority for 10 mu M trabedersen vs chemotherapy (p=.10). Median survival for 10 mu M trabedersen was 39.1 months compared with 35.2 months for 80 mu M trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged <= 55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 mu M trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 mu M trabedersen (43%) and 10 mu M trabedersen (27%). Superior efficacy and safety for 10 mu M trabedersen over 80 mu M trabedersen and chemotherapy and positive risk-benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.