[18F]Dabrafenib Molecular Imaging in Melanoma Brain Metastasis
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|ClinicalTrials.gov Identifier: NCT02700763|
Recruitment Status : Terminated (Due to the very low inlcusion rate and the current COVID-19 pandemic.)
First Posted : March 7, 2016
Last Update Posted : May 6, 2020
|Condition or disease||Intervention/treatment||Phase|
|Melanoma||Other: [18F]dabrafenib molecular imaging||Not Applicable|
Rationale: Dabrafenib is an oral protein tyrosine kinase inhibitor which specifically targets mutated BRAF protein. It is used in the treatment of metastatic melanoma with evidence of a BRAF V600 mutation in genomic material. However, in this group of patients often a heterogenic response to treatment is seen. Heterogeneity in drug accumulation in the tumor could be responsible for the observed differences in treatment response between lesions and between patients. Besides poor tumor accumulation of the drug, heterogeneous expression of the drug target, B-Raf protein, between patients and between lesions within a single patient could account for heterogeneity in treatment response.
PET imaging with radioactively labeled carrier-added [18F]dabrafenib (low specific activity) as the tracer might be a useful tool to show the distribution pattern and kinetics of the native drug; in particular PET can be used to determine if dabrafenib can cross the blood-brain barrier (BBB) and accumulate in brain metastases.
Since the behavior of [18F]dabrafenib in patients is hitherto unknown, first a feasibility study is needed. In this feasibility study, we will use low specific activity [18F]dabrafenib, for which a labeling procedure has already been developed, to determine the whole body distribution and kinetics in brain metastases in metastatic BRAF V600 mutation positive melanoma patients.
Study design: This study is a feasibility study for the use of [18F]dabrafenib as a PET tracer, in 10 patients. Patients who will be eligible for this study are at least 18 years of age. They are all diagnosed with metastatic melanoma with presence of metastasis to the brain and should have a positive BRAF V600 mutation status. In addition, patients should be naïve to treatment with a BRAF or MEK inhibitor.
Interventions: A [18F]dabrafenib PET/CT scan and an MRI scan of the brain will be performed at baseline, 7 days or less before the start of treatment with oral dabrafenib. CT and MRI are part of the regular care. The PET procedure commence with the injection of approximately 200 MBq [18F]dabrafenib, which is followed by a 60 minutes dynamic PET scan of the brain and thereafter a total-body PET scan (toe to head). During the dynamic PET scan of the brain, arterial blood sampling and analysis of plasma metabolites will be performed. Treatment response will be monitored as part of the regular treatment (CT for thorax/abdomen and MRI for brain) after 4 weeks. In addition, a single venous blood sample will be collected for isolation of circulating tumor DNA. Immunohistochemical staining for mutated B-raf protein will be performed on tumor tissue, either derived from a fresh biopsy or from a preexisting tumor specimen.
Nature and extent of burden and risk associated with participation, benefit and group relatedness: Patients who will participate in this study will receive a dynamic PET/CT scan of the brain, a static total-body PET/CT scan and an MRI scan of the brain at baseline. After 4 weeks they receive a CT scan of chest and abdomen and a MRI scan of the brain. All CT and MRI scans are part of regular care. The PET/CT scan, which is a study procedure, carries a radiation burden of 4.1 mSv. This constitutes an intermediate risk, based on criteria of the International Commission on Radiological Protection. For the purpose of pharmacokinetic modeling, an arterial catheter will be placed which is an invasive procedure. Expected adverse events will be identical to that of unlabeled dabrafenib. Patients do not directly benefit from the study, but their participation helps to get more insights in the pharmacokinetics of dabrafenib and its role in the treatment of brain metastases.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||1 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||PET Imaging of [18F]Dabrafenib Distribution and Kinetics in Brain Metastasis in Patients With BRAF Positive Metastastic Melanoma. A Feasibility Study.|
|Actual Study Start Date :||December 6, 2016|
|Actual Primary Completion Date :||April 2020|
|Actual Study Completion Date :||April 2020|
Experimental: [18F]dabrafenib molecular imaging
A [18F]dabrafenib PET scan will be performed at baseline (7 days or less before the start of treatment with oral dabrafenib).
Other: [18F]dabrafenib molecular imaging
A [18F]dabrafenib dynamic PET scan of the brain (60 minutes) and static total body PET scan will be performed at baseline.
- Absolute uptake of [18F]dabrafenib [ Time Frame: 60 minutes ]Determination of the absolute uptake (Standard uptake value (SUV)) and kinetics (time-activity curves, volume of distribution) of [18F]dabrafenib in normal brain and brain metastasis.
- Heterogeneity of [18F]dabrafenib uptake of tumor lesions and kinetics in the brain [ Time Frame: Baseline ]Analysis of heterogeneity in [18F]dabrafenib accumulation and kinetics between lesions within one organ (brain; intra-patient heterogeneity).
- Intra-patient heterogeneity in [18F]dabrafenib uptake of tumor lesions [ Time Frame: Baseline ]Analysis of heterogeneity in [18F]dabrafenib accumulation between lesions in different organs including brain metastases (total body imaging; intra-patient heterogeneity).
- Inter-patient heterogeneity in [18F]dabrafenib uptake of tumor lesions [ Time Frame: baseline ]Analysis of heterogeneity in [18F]dabrafenib accumulation between all lesions in different patients (Inter-patient heterogeneity).
- Correlation of [18F]dabrafenib uptake with response to dabrafenib treatment of tumor lesions [ Time Frame: 4 weeks ]Correlation of accumulation of [18F]dabrafenib in melanoma metastasis with response to treatment according to the RECIST criteria (response evaluation with MRI brain and CT of chest and abdomen after 4 weeks).
- Correlation between absolute tumor tracer uptake of [18F]dabrafenib and immunohistochemical staining with VE1 mAb (anti V600-mutated BRAF). [ Time Frame: Baseline ]Correlation between absolute tumor tracer uptake of [18F]dabrafenib and positive immunohistochemical staining using specific MAB's against mutated B-Raf protein.
- Correlation between absolute tumor tracer uptake of [18F]dabrafenib and BRAF V600 mutation load as maesured in circulating tumor DNA (ctDNA). [ Time Frame: Baseline ]Correlation between absolute tumor tracer uptake of [18F]dabrafenib and BRAF V600 mutation load in ctDNA as measured by quantitative PCR.
- Comparison between direct DNA sequencing and Droplet Digital Polymerase Chain Reaction (ddPCR) for BRAF mutation detection. [ Time Frame: Baseline ]Correlation between BRAF mutation status as determined by direct DNA sequencing using tumor tissue samples (golden standard) and ddPCR using ctDNA.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02700763
|University Medical Center Groningen|
|Groningen, Netherlands, 9713 GZ|
|Principal Investigator:||Geke AP Hospers, MD, PhD||University Medical Center Groningen|