Results of G004, a phase IIb study in recurrent glioblastoma patients with the TGF-b2 targeted compound AP 12009

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1553 Background: In high-grade glioma (HGG), TGF-β2 expression strongly correlates with tumor grade and is highly predictive of disease outcome. The compound AP 12009 inhibits TGF-β2 expression. Preclinical results revealed strong multimodal activity including reversal of TGF-β induced immunosuppression, inhibition of tumor cell migration and proliferation. In 3 preceding phase I/II dose escalation studies, 24 HGG patients had been treated with AP 12009. Methods: G004 is an international open-label, actively controlled, dose finding phase IIb study. Objective is a comparison of two doses of AP 12009 and standard chemotherapy for efficacy and safety. 145 patients with histopathologically confirmed recurrent anaplastic astrocytoma (AA, WHO grade III) or glioblastoma (GBM, WHO grade IV) were randomized into one of 3 treatment arms. 134 patients received treatment AP 12009 10μM, AP 12009 80μM or standard chemotherapy (TMZ or PCV). AP 12009 was applied locoregionally by convection-enhanced delivery during a 6-month active treatment period with 7-day-on, 7-day-off cycles. Primary endpoint is tumor response by local and central MRI reading. All patients have completed active treatment. Follow-up for survival and tumor response assessed by local and central MRI reading is ongoing. Results: Here we report on patients with recurrent GBM (AA see separate Abstract). 96 GBM patients (37% female, 63% male; median age 51 years, range 20–74; median Karnofsky performance status 90, range 70–100) have been treated. 63 GBM patients received AP 12009 (28 pt. 10 μM, 35 pt. 80 μM), 33 patients received standard chemotherapy. Data were evaluated by an independent Data and Safety Monitoring Board. Up to now, in 89 patients treated with AP 12009 (AA and GBM patients) 6 SAEs possibly related to the study drug and 37 procedure related SAEs (92% mild or moderate) were documented. Several long-term tumor responses were observed by local MRI reading. Exact response rates are being determined by central reading. Conclusions: Responses in patients treated with AP 12009 in both AA and GBM patients are long lasting with a good quality of life. Phase III clinical trials in AA and GBM patients are currently in preparation. [Table: see text]

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