Guiding GC1008 Treatment of Primary Brain Tumors by 89Zr-GC1008 PET Imaging.
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.
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 Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Part 1, Biomarker imaging: 89Zr-GC1008 PET imaging in patients with suspicion of a malignant glioma: Primary endpoint: - Quantification of uptake of 89Zr-GC1008 as determined by PET imaging. The data obtained from the PET-scans will be quantified as standardized uptake value (SUV).
Annemiek ME Walenkamp, MD, PhD
University Medical Centre Groningen
Netherlands: Medical Ethics Review Committee (METC)