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