Disseminated Malignant Neoplasm Clinical Trial
Official title:
Measurement of Tumor Kinase Inhibitor Concentrations Using PET Imaging in Patients With Advanced Solid Malignancies
The investigators hypothesize that response to kinase inhibitors is dependent on achieving
pharmacological active drug levels in tumor tissue and that quantitative PET imaging can
predict kinase inhibitors tumor concentrations. The ultimate aim is to develop a
quantitative PET based imaging tool to differentiate between patients who will respond to
therapy with kinase inhibitors.
The main objective of this study is to determine whether tumor concentrations of kinase
inhibitors at pharmacological active doses can be predicted from PET studies using tracer
amounts (microdosing) of corresponding radiolabeled kinase inhibitors. This objective
includes the development and validation of pharmacokinetic models for radiolabeled kinase
inhibitors as well as validation of the microdosing concept for kinase inhibitors.
Rationale: Multiple agents targeting specific signaling proteins important for tumor growth
and angiogenesis, including (tyrosine) kinase inhibitors and monoclonal antibodies, have
been developed and have reached clinical approval. In general, however, these targeted
agents induce a response only in a subgroup of cancer patients, while all are exposed to
potential toxic therapies. Prior to treatment, it is unknown which patients will respond and
why kinase inhibitors are only effective in some, but not all, patients. Clearly, there is a
need for a non-invasive in vivo technique to identify those patients who may benefit from
treatment with a specific drug.
Positron emission tomography (PET) is a non-invasive technique that enables quantitative
measurements of molecular pathways and interactions with picomolar sensitivity and, as such,
it has the potential to fulfill the need mentioned above. We expect that response to kinase
inhibitors is dependent on achieving active drug levels in tumor tissue. Currently,
intratumoral kinase inhibitor levels are being investigated at our institution (ICK study).
However, these measurements require fresh tumor biopsies. We hypothesize that radiolabeled
kinase inhibitor PET imaging can quantify concentrations of labeled drug in tumor lesions,
thereby avoiding burdensome biopsies in the future.
Objective: The main objective of this study is to determine whether tumor concentrations of
kinase inhibitors at pharmacological active doses can be predicted from PET studies using
tracer amounts (microdosing) of corresponding radiolabeled kinase inhibitors. This objective
includes the development and validation of pharmacokinetic models for radiolabeled kinase
inhibitors as well as validation of the microdosing concept for kinase inhibitors.
The secondary objectives include exploration whether kinase inhibitor kinetics depend on
perfusion (as measured by [15O]water PET) or size (as measured by diagnostic CT/MRI) of
tumor lesions, to investigate the presence of a sink that accumulates kinase inhibitor, and
to investigate (in)activation of key pathways targeted by the specific kinase inhibitor.
Study design: Single center, non-randomized, interventional proof of concept study.
Study population: Adult patients with advanced, biopsy accessible tumors for whom standard
palliative treatment with the kinase inhibitor investigated in this study, i.e. erlotinib
and sorafenib, is indicated.
Intervention: Patients will be treated with the kinase inhibitor according to standard
treatment. [11C] kinase inhibitor PET (i.e. sorafenib and erlotinib in this study, with the
aim to investigate others in future studies) and [15O]water PET will be performed before and
after two weeks of treatment. Tumor biopsies will be performed before and during therapy.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness: Enrollment in this study will require two tumor biopsies, 2x [11C] kinase
inhibitor PET, 2x [15O]water PET and arterial blood sampling. The biopsies may cause
physical discomfort. During therapy, follow-up will include standard laboratory analysis as
well as regular visits to the outpatient clinic. The radiation exposure is acceptable.
Patients treated with a kinase inhibitor as standard therapy may benefit from disease
regression or stabilization as it has proven clinical benefit in the patient population
under investigation. The results of this kinase inhibitor PET imaging study will be strongly
supportive for the development of non-invasive, personalized treatment strategies thereby
avoiding 1) cumbersome tumor biopsies, 2) unwanted exposure to potentially toxic drugs and
3) costly therapy without clinical benefit.
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