Trial Information

Mabtornib Protocol.Vascular, Metabolic and Hormonal Effects of Angiogenesis Inhibitors and Epidermal Growth Factor Receptor Inhibitors

Background

In recent years, multiple new agents have been developed that inhibit angiogenesis and the
epidermal growth factor receptor (EGFR) signalling pathway.

The cell signalling routes that are inhibited by these agents however are not only active in
tumour formation but are also involved in physiological processes in normal tissue and
organs. This means that these drugs do not only have an anti tumour effect but also modify
several physiological processes that lead to side effects. Little is known about these side
effects that generally are less severe than side effects of cytotoxic chemotherapy, but
because targeted therapy is often administered for prolonged periods of time, these side
effects can seriously affect quality of life.

Objectives

Primary objectives

1. To determine the characteristics, frequency and severity of vascular, metabolic and
hormonal side effects of angiogenesis and EGFR inhibitors.

Secondary objectives

1. To investigate if steroid profile, indol profile, concentrations of catecholamines and
metanephrines or thyroid antibodies change during treatment with angiogenesis and EGFR
inhibitors.

2. To investigate if known biomarkers change during treatment.

3. To investigate whether vascular function changes during treatment with angiogenesis
and EGFR inhibitors.

4. To determine if changes in skin autofluorescence and development of AGE's occur during
treatment with angiogenesis and EGFR inhibitors.

5. To determine whether changes in factors mentioned under secondary objectives 1-4 are
correlated with side effects of targeted therapy and/or response to angiogenesis and
EGFR inhibitors.

6. To evaluate if polymorphisms in genes involved in pathways mentioned under 1-4
associate with toxicity and efficacy of angiogenesis and EGFR inhibitors.

Study design and population

This is a prospective, explorative observational cohort study in patients treated with
angiogenesis or EGFR inhibitors. Concomitant chemotherapy, immunotherapy or radiotherapy is
allowed. Patients must be 18 years or older at start of treatment and must be willing to
give written informed consent.

Primary study parameters

Patients will be evaluated for vascular changes by measuring

- 24-hour ambulatory blood pressure

- nail fold capillary microscopy

- skin autofluorescence at 3 time points: before start of treatment, and after 3 and
after 6 weeks of treatment. Patients will also be asked to measure their blood pressure
at home twice a day, for 6 weeks. Metabolic and hormonal changes and investigation of
biomarkers will be done by blood and urine analyses every 3 weeks for the first 3
months, every 6 weeks up to 6 months and every 3 months thereafter.

Changes in vascular, hormonal and metabolic status will be related to clinical side effects
and to response to treatment.

Secondary study parameters

When clinically relevant differences in side effects and response to treatment are found
among patients treated with the same agent, DNA analysis will be carried out to investigate
if changes in candidate genes are related to these differences.

Burden and risks associated with participation, benefit and group relatedness

The minimal invasive tests will be performed during routine outpatient visits. As far as
known no serious adverse events are linked to the described study procedures. With this
study we hope to get insight into the characteristics, frequency, severity and underlying
mechanisms of angiogenesis and EGFR inhibitor induced vascular, metabolic and hormonal side
effects and to find usable surrogate markers for efficacy of treatment. Eventually, this may
contribute to the early detection of vascular, metabolic and hormonal changes, to the design
of intervention strategies for side effects and to better patient selection for angiogenesis
and EGFR inhibition.