Pharmacokinetics of bevacizumab in patients with malignant ascites

Malignant ascites is an accumulation of fluid intra-abdominal as a result of
peritonitis carcinomatosa. Patients usually complain about an extending belly,
pain, decreased appetite and dyspnoea. If treatment with anti-tumor therapy is
not an option, paracentesis leads to a decrease in symptoms. However, if no
anti-tumor treatment is provided, fluid re-accumulation will occur. As a
result, paracentesis should be performed regularly to improve the quality of
life. However, paracentesis is an invasive, painful procedure, which can become
technically difficult the more paracentesis have been performed.
There are several factors involved in the development and growth of tumors.
Angiogenesis, the forming of new blood vessels is one of these factors. New
vasculature allows tumor cells to execute their critical growth by supplying
the tumor with nutrients and oxygen, disposal of metabolic waste products and
provides route for metastatic spreading 1, 2. An important factor involved in
angiogenesis is VEGF-A. VEGF-A is released by tumor cells and induces tumor
neovascularization. Over-expression of VEGF-A occurs in many human tumor types.
The local VEGF-A production leads to paracrine effects in the tumor, resulting
in angiogenesis and growth exploration. In malignant ascites high levels of
VEGF-A are found. Chemical molecules which can block the tyrosine kinase
function of VEGF-receptors and antibodies binding to the ligand and the
receptor have been developed. Bevacizumab is one of these antibodies, which has
shown to be acitve in colon, breast and lungcancer.
In case reports, bevacizumab was active in the treatment of malignant ascites.
Bevacizumab was given intravenously in those patients. Whether local
(intraperitoneal) administered bevacizumab is as effective remains to be
investigated.

To study pharmacokinetics of intravenously and intraperitoneally administered
bevacizumab in patients with malignant ascites for whom there is no systemic
anti-tumour treatment available.

This is an observational study, which studies the pharmacokinetics of
intravenously or intraperitoneally administered bevacizumab in patients with
malignant ascites.
Patients with malignant ascites, who do not receive systemic anti-tumour
treatment, will be treated with bevacizumab therapy. The distribution kinetics
of 111In-bevacizumab will be assessed. This distribution of 111In-bevacizumab
can be used as a surrogate marker for the total bevacizumab distribution. The
patients will receive one injection of 111In-bevacizumab in combination with a
therapeutic dose of bevacizumab. Serum and ascitic fluid samples will be
collected at T=30 minutes, T=60 minutes, T=3 hours, T= 6 hours, T=24 hours,
T=48 hours, T=96 hours, T=120/144 hours and T=168 hours to assess
pharmacokinetics. The toxicity of intraperitoneally and intravenously
administered bevacizumab will be evaluated by measuring clinical and
hematological parameters.

5 patients will be given bevacizumab (therapeutic dose in combination with
radioactive tracer dose) intravenously and 5 patients will be given bevacizumab
intraperitoneally.

Bevacizumab will be administered in a therapeutic dose (7,5 mg/kg).
Side-effects of bevacizumab are leukopenia, diarrhea, hypertension, thrombotic
events, deep thromboplebitis, pulmonary embolus, bleeding, proteinuria and
gastro-intestinal bleeding. These events are for the most part mild to moderate
in severity and clinically manageable (hypertension, proteinuria, minor
bleeding) or occur uncommonly (wound healing complications, GI perforations and
arterial thrombosis). Whether or not a tracer dose of 111In-bevacizumab can
induce any adverse effect is unknown, but it is very unlikely and not expected.
Although no toxicity is expected from the tracer-dose, side-effects of the
therapeutic dose bevacizumab can be expected. These will be scored according to
the Common Toxicity Criteria version 3.0.

Administration of the tracer dose 111In-bevacizumab entails radiation for the
participating patients. It has been calculated that a dose of 10 MBq will lead
to a radiation load of 1,8 mSv. For comparison purposes, a CT-abdomen will lead
to a radiation dose of 10-15 mSv. The poor prognosis of this patient group (5
year survival < 1%) and the potential new information given by this study makes
this radiation load acceptable.