Primary objective is to determine the absolute uptake (Standardized uptake value (SUV)) and kinetics (time-activity curves) of [18F]dabrafenib in normal brain and brain metastasis. Secondary objectives are to analyze heterogeneity in [18F]dabrafenib…
ID
Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters are standardized uptake value and distribution
volume. The last derived from kinetic modeling using the arterial input of the
tracer and plasma metabolites measurements.
Secondary outcome
Both inter- and intrapatient heterogeneity will be determined for the SUV's of
the diffent lesions seen on PET. For response evaluation anatomical
measurements of target lesions according to the RECIST 1.1 criteria will be
used. The response will be correlated to drug accumulation (absolute uptake of
tracer). In addition, immunohistochemical staining for B-raf and mutational
load of BRAF measured by ddPCR will be correlated to absolute tracer uptake.
Background summary
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 objective
Primary objective is to determine the absolute uptake (Standardized uptake
value (SUV)) and kinetics (time-activity curves) of [18F]dabrafenib in normal
brain and brain metastasis.
Secondary objectives are to analyze heterogeneity in [18F]dabrafenib
accumulation and kinetics between different lesions within the brain, between
lesions in different organs and between lesions in different patients. Other
secondary objectives are to correlate drug accumulation to response to
treatment (based on follow up scans after 4 weeks) and to correlate tracer
uptake to immunohistochemical staining of biopsy samples with monoclonal
antibodies against mutated B-Raf protein. In addition, the correlation between
mutational load of BRAF as measured with Droplet Digital PCR and tracer uptake
is a secondary objective.
Study design
This study is a feasibility study for the use of [18F]dabrafenib as a PET
tracer, in 10 patients. Patients will receive a dynamic PET scan of the brain
with bloodsampling and a static total body PET scan before start with
dabrafenib. The PET-scan will be accompanied by a CT scan of chest and abdomen
and a MRI scan of the brain. For study purposes one venous blood sample of 10ml
will be obtained. If feasible a biopsy will be taken from an easy accesible
lesion.
Intervention
A [18F]dabrafenib PET/CT scan and an MRI scan of the brain will be performed at
baseline, which is 7 days or less before the start of treatment with oral
dabrafenib. 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. 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.
Study burden and risks
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 as part of regular treatment. The PET 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. Besides PET
imaging, a single venous blood sample will be taken which will give minor
discomfort. In addition, patients will be asked to give consent for a biopsy.
This is an invasive procedure. The presence of easily accessible lesions is
precondition. Although biopsies are generally considered to be safe, it could
be a painful intervention and carries the risk of bleeding at the puncture
site. 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.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
1. Has signed informed consent.
2. Older than 18 years of age.
3. Histologically confirmed cutaneous metastatic melanoma (Stage IV), including confirmed brain metastases.
4. BRAF mutation-positive (V600 E/K) melanoma as determined by standardized genetic testing.
5. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
6. Eligible for standard treatment with dabrafenib.
7. No contraindication for performing a CT scan.
8. No contraindication for performing a MRI scan of the brain.
9. Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control from 14 days prior to randomization, throughout the treatment period and for 4 weeks after the last dose of study treatment.
10. Women of child-bearing potential must have a negative serum pregnancy test (*-HCG) within 14 days of first dose of study treatment.
Exclusion criteria
1. Treatment with a BRAF or MEK inhibitor.
2. Known immediate or delayed hypersensitivity reaction to dabrafenib or excipients.
3. Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study.
4. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Grade 2 or higher from previous anti-cancer therapy, except alopecia.
5. Any serious or unstable pre-existing medical conditions (i.e, diabetes mellitus, hypertension, etc), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.
6. Altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent, unless a legally acceptable representative could provide informed consent.
7.Pregnant or nursing females.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004667-21-NL |
| ClinicalTrials.gov | NCT02700763 |
| CCMO | NL50793.042.16 |