Safety and Imaging Study of GC1008 in Glioma
Condition: Primary Brain Tumors
MeSH terms: Brain Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      Brain tumors account for only 2% of all cancers but result in a disproportionate share of
      cancer morbidity and mortality. The five-year survival rates for the most common histologic
      subtypes, anaplastic astrocytoma and glioblastoma (glioblastoma multiforme, GBM), are 30% and
      10%, respectively.

      Drugs affecting transforming growth factor-β (TGF-β) might be of great interest for malignant
      glioma treatment. TGF-β is an oncogenic factor in advanced tumors where it induces
      proliferation, angiogenesis, invasion, and metastasis as well as suppresses the antitumoral
      immune response. In addition TGF-β and its TGF-β receptors, TβRI and TβRII, are overexpressed
      in GBMs. TGF-β signaling is involved in multiple steps of GBM development. GC1008 is an
      antibody that is capable of neutralizing TGF-β and may therefore offer a new treatment option
      for patients with malignant glioma.

      For therapeutic success, it may be essential for GC1008 to reach the target site, in this
      case located in the brain. We will be able to prove this with 89Zr-GC1008 PET imaging. This
      imaging method also allows quantification of the amount of GC1008 reaching the tumor.

      This study consists of 2 parts. In part 1, patients with a suspicion of a malignant glioma
      undergo an 89Zr-GC1008 PET scan before standard (surgical)treatment. In part 2, patients with
      relapsed malignant glioma will undergo an 89Zr-GC1008 PET scan and will be treated with
      GC1008 in a phase II study as there is no standard treatment for these patients.

      We hypothesize that GC1008 uptake in brain tumors can be visualized and quantified using the
      89Zr-GC1008 PET scan and GC1008 might offer a new treatment option for patients with relapsed
      malignant gliomas.
    

Detailed description: 
      Brain tumors account for only 2% of all cancers but result in a disproportionate share of
      cancer morbidity and mortality. The five-year survival rates for the most common histologic
      subtypes, anaplastic astrocytoma and glioblastoma (glioblastoma multiforme, GBM), are 30% and
      10%, respectively.

      After surgery, the standard treatment of malignant glioma is focused on cell death induction
      by DNA damage, neglecting the fact that invasion into surrounding brain tissue is a
      fundamental feature of and the major reason for treatment failure.

      Drugs affecting transforming growth factor-β (TGF-β) might be of great interest for malignant
      glioma treatment. The reason for this is the fact that TGF-β acts as a tumor suppressor in
      normal epithelial cells and early-stage tumors but transforms in an oncogenic factor in
      advanced tumors where it induces proliferation, angiogenesis, invasion, and metastasis as
      well as suppresses the antitumoral immune response. In addition TGF-β expression and its
      TGF-β receptors, TβRI and TβRII, are overexpressed in GBMs. TGF-β signaling is involved in
      multiple steps of GBM development (Golestaneh, Mishra, 2005) and invasion (Wesolowska et al,
      2008). Plasma TGF-β levels are elevated in GBM patients and decrease after surgical tumor
      resection (Schneider et al, 2006). Progression-free survival and overall survival are worse
      for malignant glioma patients with high TGF-β signaling compared with glioma patients with
      low TGF-β signaling activity (Bruna et al, 2007). All these features make TGF-β a promising
      target molecule for biological treatment approaches for GBM (Wick et al, 2006). Phase
      I/II-studies with the TGF-β2-specific antisense oligodeoxynucleotide AP12009 in malignant
      glioma showed promising results (Hau et al, 2007). Another approach to target TGF-β is with
      monoclonal antibodies, such as GC1008. GC1008 is a fully human IgG4 kappa monoclonal antibody
      capable of neutralizing all mammalian isoforms of TGF-β (i.e., 1, 2, and 3). For therapeutic
      success, it may be essential for GC1008 to reach the target site, in this case located in the
      brain. Our own data with 89Zr-bevacizumab, which is also an IgG, showed that the VEGF
      directed antibody bevacizumab penetrates the brain and is localized in brain metastases. We
      therefore expect GC1008 to reach the malignant glioma as well. In order to initiate clinical
      trials with TGF-β antibody in these patients it would clearly be of great help to prove that
      the drug arrives at the tumor site. 89Zr-GC1008 PET imaging will allow us to prove this. In
      addition, PET imaging allows quantification of the amount of GC1008 reaching the malignant
      glioma. A phase II study with GC1008 in patients with relapsed malignant gliomas will be
      initiated as currently, there is no standard treatment available for these patients.

      Study objectives:

      Part 1: Feasibility of 89Zr-GC1008 PET imaging in patients with suspicion of a malignant
      glioma to assess if GC1008 penetrates into the brain tumor and to quantify its uptake.

      Part 2: 89Zr-GC1008 PET imaging in patients with relapsed malignant glioma and phase II
      extension study with therapeutic GC1008 in these patients.

      For part 1, 12 patients will be included. For part 2, 12-20 patients will be included.
    

Intervention name(s): 89Zr-GC1008; GC1008
Intervention type(s): Other; Drug
Intervention description(s): radioactive labeled GC1008, intravenous use, 37 MBq total; 5 mg/kg intravenous use
Other intervention name(s): 89Zr-fresolimumab; fresolimumab
Intervention MeSH terms: Antibodies, Monoclonal
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: GC1008; PET imaging; primary brain tumors; recurrent high grade glioma's