Exploration of VEGF expression in paediatric high grade glioma and diffuse intrinsic pontine glioma using 89Zirconium-bevacizumab imaged by PET

Paediatric high grade gliomas (pHGG) including diffuse intrinsic pontine
gliomas (DIPG) have a poor prognosis. pHGG highly express vascular endothelial
growth factor (VEGF), which is involved in mitogenic, angiogenic, and
permeability enhancing processes. The monoclonal antibody bevacizumab inhibits
VEGF-A and showed efficacy in adult glioma and to a lesser extend in pHGG.
Bevacizumab can be labelled to Zirconium-89 for drug distribution and
non-invasive target expression studies imaged by PET. Zirconium-89 is a
positron emitter with a long half-time which is preferable because of its
safety, purity and stable binding to its antibody and relatively low costs. In
adults, 89Zr-bevacizumab could be used safely in humans and was shown to
visualise targets precisely. In our study, bevacizumab is microdosed at 1/100th
of the therapeutic dose in pHGG and DIPG. PET-imaging of 89Zr-bevacizumab may
help to select future patients more likely to respond to bevacizumab therapy.

Determining VEGF expression in pHGG and DIPG using 89Zr-Bevacizumab

This a multicenter diagnostic trial. All patients receive 10 ml of 89-zirconium
(18.5mbq)- bevacizumab (2mg) i.v.. 89Zr bevacizumab PET scans will be performed
at 1, 72 and 144 hours post-injection (p.i). Each PET scan will be preceded by
a low-dose CT. Following the CT, a 10 min static PET-CT scan will be performed
covering the brain, followed by a whole-body PET scan (4 min per bed position,
total duration circa 25 min) to determine the 89Zr-biodistribution. After
defining the Volume of Interest by co-registration of a T1 MRI, tumor to
background ratios and Standardized Uptake Values will be calculated. If the
Zirconium-89 dose (18.5mbq) appears to be insufficient to obtain good quality
images, the zirconium dose (without increasing the bevacizumab dose) can be
increased up to 40 mbq in subsequent patients.

89-Zr bevacizumab once

Risks: This is a diagnostic study in patients with a lethal disease.
Bevacizumab, used as a diagnostic, is dosed 1/100th of the therapeutic dose
(10mg/kg) and therefore no adverse events of bevacizumab are expected.
All patients have been or will be irradiated, usually with a total dose of
54Gy. The radiation burden added by this study is therefore, negligible.
Patients receive a total dose of 0.9 MBq/kg, 0.1 mg/kg 89Zr-bevacizumab, which
results in an expected radiation dose of 20-45 mSv. An additional 3mSv will be
added by the low dose CT scans for each whole body PET/CT examination. The
total radiation burden of three whole body PET/CT examinations will be
29-50mSv. For comparison, the worldwide average background dose for a human
being is about 2 mSv per year. In case the images in the first patient(s)
appear to be of inferior quality, the zirconium-89 dose can be increased up to
37 Mbq. The total radiation burden will then be maximum 50mSv. A previous study
in patients with head and neck cancer did not report any zirconium-related
toxicity in 20 patients who received 89Zr-labeled anti-CD44v6 (a monoclonal
antibody), followed by surgery.
In general, allergic reactions may occur at non-therapeutic doses and therefore
patients will be monitored carefully for a few hours from time of injection.
However, in several zirconium-89 studies including an ongoing UMCG
89Zr-bevacizumab study with more than 20 adult patients being enrolled so far,
no allergic reactions were observed (personal communication dr. L. de Vries).

Burden: All participants receive an i.v. cannula and undergo three whole body
PET scans in one week. They have to lay down quiet for 30 minutes for each
scan. No anaesthesia will be used. Our standardised training program enables
children from four years to undergo MRI without major problems. An advantage of
PET is that the quality of the images is less influenced by small movements
compared to MRI. To reduce the patient burden, we have chosen not do perform
blood collections, which is usual in adult PET studies.

Benefit: Subjects do not have a direct personal benefit from this diagnostic
study, although they can be treated on an individual base with bevacizumab in
case of a positive PET scan.

Group relatedness: We are certainly aware of this burden, but in our opinion,
the scientific value of this project outweighs this concern, because selection
of patients may lead to effective personalized treatment cancer and helps to
prevent the administration of inactive drugs and the accompanying side effects
in the future. Studies in pHGG are necessary since biology including receptor
kinase expression clearly differs from adult HGG. These PET-labelling studies
are not only applicable to children with HGG and DIPG, but in fact to all
children with solid tumours.