Trial Information

Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities

Rationale: In the past decade multiple agents targeting specific signaling proteins
important for tumor growth, including (tyrosine) kinase inhibitors, EGFR inhibitors, mTOR
inhibitors and BRAF inhibitors, or agents that modulate the immune response such as
ipilimumab, have been developed and have reached clinical approval. Initially it was
anticipated that these agents would be active without causing major toxicities, but recent
clinical experiences have changed these expectations. Diagnostic tools to predict whether a
patient will develop toxicity to targeted agents are not yet available. Our general
hypothesis is that immunophenotyping studies combined with (phospho) proteomic and kinase
activity profiling in normal tissue before and during treatment with targeted agents may
provide more insight in underlying causative mechanisms of toxicity and provide potential
biomarkers for clinical use to predict for toxicity.

The investigators hypothesize that targeted therapy- induced toxicity is caused by
interference with normal physiological homeostasis at the tissue level. To date, preclinical
strategies to predict for clinical toxicities of targeting therapies are lacking.

This study is intended to (1) explore the biological (immunological) mechanisms of targeted
agents at the systemic and local tissue level in relation to toxicity (2) determine if
off-target receptor kinase inhibition in normal cells and tissues is related to toxicity of
the treatment and (3) try to identify novel biomarker(s) predictive of toxicity.

Objective: The main objective of this pilot study is to determine the biological impact of
treatment with targeted agents at the systemic and local tissue level in relation to
toxicity.

Study design: Single center, non-randomized, interventional pilot study with feasibility
analysis after enrollment of 20 patients.

Study population: Adult patients with advanced solid tumors, for whom standard palliative
treatment with targeted agents as monotherapy is indicated, including antiangiogenic
tyrosine kinase inhibitors, EGFR inhibitors, mTOR inhibitors, BRAF inhibitors and
ipilimumab.

Intervention: Patients will be treated with targeted therapies according to the clinical
standard guidelines. At this point, five targeted therapies with considerable skin and
gastrointestinal toxicities have reached widespread clinical use and therefore
"antiangiogenic" tyrosine kinase inhibitors, EGFR inhibitors, mTOR inhibitors, BRAF
inhibitors and ipilimumab will be investigated in this study. After feasibility analysis in
the first twenty patients, twenty more patients will be included in each of the five drug
cohorts. Biopsies will be performed to determine possible immunohistochemical and
histopathological changes in normal tissue, possible immunomodulatory changes as expressed
by Tcell phenotyping and cytokine profiling and to compare tissue (phospho) proteomic and
kinase activity profiles before and during therapy and also at the development of toxicity.

Main study parameters/endpoints: The main objective is to explore the biological impact of
treatment with targeted agents at the systemic and local tissue level in relation to
toxicity. This objective will be assessed by studying in normal tissue whether treatment
with targeted agents induces significant changes in normal tissue of (1) histopathology,
such as differences in the presence of infiltrating immune cells, (2) (phospho)proteomic
profiles and (3) kinase activity profiles. Secondary objectives are (1) to perform
pharmacokinetics and to study whether serum peptide profiles and systemic circulating
immune cells and cytokine profiles in patients during treatment with targeted agents are
related to toxicity and (2) to identify novel biomarkers predictive of treatment induced
toxicity based on pretreatment systemic or local tissue phenotypes.

Nature and extent of the burden and risks associated with participation, benefit and group
relatedness: Enrolment in this study is possible when the indication to receive standard
targeted therapy has been determined. Adverse events as a result of this standard treatment
may occur. Biopsies of skin, oral mucosa, colon mucosa once prior to and during treatment
will be taken. If toxicity develops, a re-biopsy of the affected area will be taken. These
biopsies may cause physical discomfort. During therapy, follow-up will include laboratory
analysis on a visit to the outpatient clinic. Results of this study may provide new clues
for prediction and treatment of targeted therapy induced toxicity