Targeted therapy selection based on tumor tissue kinase activity profiles for patients with advanced solid malignancies, an exploratory study

In the past decade multiple agents that target specific signalling proteins
important for tumor growth and angiogenesis have been developed and have
reached clinical approval. Thus far, it is unclear which patients will respond
to these agents and why targeted agents are only effective in a subgroup of
cancer patients. Adequate diagnostic tools to predict whether a patient will
respond are not yet available. It is of crucial importance to develop new
clinical tests to determine which patients will respond to these targeted
agents. In order to select patients for a targeted therapy, several profiling
approaches have been explored but to date no adequate and reliable test to
predict for response is available. It is assumed that responses to these agents
depend on specific receptor and protein signalling activities in tumor tissues.
We hypothesize that inhibitory activity of tyrosine kinase inhibitors on kinase
activity in a tumor biopsy will correlate to and predict for response to
treatment. Therefore, we propose that kinase activity profiling may be a
potential clinical diagnostic tool to predict for tumor response to targeted
therapy with tyrosine kinase inhibitors (TKI*s).

To select targeted treatment based on ex vivo kinase activity inhibition
profiles to targeted agents of tumor tissue from patients with advanced cancer
for whom no standard treatment is available.

Non-randomized intervention study.

Patients will undergo a tumor biopsy for *ex vivo* treatment of this tumor
tissue with clinically available targeted (antiangiogenic) tyrosine kinase
inhibitors, such as sunitinib, sorafenib and erlotinib. Inhibition of the
kinase activity profiles of ex vivo treated samples will be determined by
comparison to their untreated control. If incubation with a targeted agent
results in significant signal inhibition, treatment with the most potent
inhibitor in this assay will be proposed to the patient. In case of equal
inhibition, the least toxic agent will be selected for treatment.

Enrolment in this study will require a tumor biopsy prior to treatment with
tyrosine kinase inhibitors. If a tumor biopsy is technically feasible, patients
can be given study information for this study. This biopsy and, if necessary,
supporting procedures may cause physical discomfort.
In general reversible side effects of the kinase inhibitor and adverse events
as a consequence of the tissue biopsy may occur.
During therapy, follow-up will include laboratory analysis on regular visits to
the outpatient clinic according to standard treatment with these type of
agents.

As a result of the *personalized* therapy selection, advanced cancer patients
lacking standard treatment options may benefit from potential disease
regression or stabilization by agents that have shown to be able to result in
clinical benefit in other tumor types.
In general, identifying additional treatment options that are likely to be
effective beforehand may increase life expectancy of advanced cancer patients
and will prevent toxicity of therapy that turns out to be ineffective or from
which efficacy may not be expected, such as in phase I clinical studies with
experimental agents. In addition, this response predicting strategy may be more
cost-effective.