Phase IIb Clinical Trial With TGF-β2 Antisense Compound AP 12009 for Recurrent or Refractory High-grade Glioma

Multi-national, Open-label, Active-controlled, Randomized Dose-finding Study to Evaluate Efficacy of 2 Doses of AP 12009 in Recurrent Glioma, Administered Intratumorally as Continuous High-flow Microperfusion Over 7 Days Every Other Week

In this multinational dose finding Phase IIb study the efficacy and safety of two doses of AP 12009 compared to standard chemotherapy (temozolomide or PCV) is investigated in adult patients with confirmed recurrent high-grade glioma.

The purpose of this study is to compare the safety and efficacy of two doses of AP 12009 and standard chemotherapy in adult patients with recurrent high-grade glioma (anaplastic astrocytoma [AA], WHO grade III; or glioblastoma [GBM], WHO grade IV). AP 12009 is a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of human transforming growth factor-beta2 (TGF-beta2). The growth factor TGF-beta plays a key role in malignant progression of various tumors by inducing proliferation, invasion, metastasis, angiogenesis and escape from immunosurveillance. It has been shown that in a number of tumor types the degree of TGF-beta production strongly correlates with tumor grade and stage. In patients with high-grade glioma, the TGF-beta2 overexpression is associated with disease stage, clinical prognosis and the immunodeficient state of the patients.

Inclusion Criteria:

• Histopathologically confirmed diagnosis of recurrent or refractory high-grade glioma (anaplastic astrocytoma, WHO grade III; or glioblastoma, WHO grade IV)
• Supratentorial localization
• No more than two chemotherapy regimens including radiochemotherapy since primary diagnosis
• Eligible for either TMZ or PCV treatment
• Recovery from acute toxicity caused by any previous therapy
• Adequate organ functions
• KPS at least 70%

Exclusion Criteria:

• Tumor surgery within 2 weeks prior to study entry
• Radiation therapy within 8 weeks prior to study entry
• Chemotherapy within 4 weeks prior to study entry (nitrosureas: 6 weeks)
• No more than 3 mg/day dexamethasone (or equivalent) at baseline
• Prior TGF-beta targeted therapy or tumor vaccination
• Baseline MRI shows mass effect
• Known active infection with HIV, HBV, or HCV; acute viral, bacterial, or fungal infection
• Significant psychiatric disorders/legal incapacity or a limited legal capacity