The primary objective of this study is to obtain clinical proof of principle that the addition of a PgP/BCRP inhibitor increases CNS concentrations of tyrosine kinase inhibitors by inhibition of drug efflux transporter function in the blood brain…
ID
Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary parameter of this study is to obtain clinical proof of principle
that the addition of a PgP/BCRP inhibitor increases CNS concentrations of TKIs
by inhibition of drug efflux transporter function in the blood brain barrier.
This will be determined by measuring the difference in estimated influx,
outflux and absolute concentrations of TKI in the brain using dynamic PET
evaluation, with and without the addition of a PgP/BCRP inhibitor.
Secondary outcome
Secondary objectives of this study are the determination of labeling
efficiency, radiochemical purity, sterility, pyrogen and radiation safety of
the newly developed radiolabeled TKI PET tracers.
Background summary
The development of brain metastases is a common phenomenon in renal cell cancer
(RCC), Non Small Cell Lung Cancer (NSCLC), and Her2 positive breast cancer. The
median overall survival of patients developing brain metastases is 3 to 6
months. More importantly, brain metastases decrease quality of life by
generating symptoms like headache, seizures and mental alterations. We
hypothesize that, when TKI treatment is combined with an inhibitor of PgP and
BCRP, such as elacridar, TKI concentrations in the central nervous system (CNS)
will increase and the development of brain metastases may be prevented.
Animal models suggest that penetration of TKIs through the blood brain barrier
(BBB) is limited, due to activity of drug efflux transporters PgP and BCRP. In
PgP knock-out (Abcb1a/1b-/-) mice, TKI drug levels in the CNS can increase
6-fold or more when compared to wild-type mice, as is demonstrated for
sunitinib, dasatinib, imatinib, lapatinib, erlotinib and sorafenib. Due to
effux of the drug by PgP and BCRP in normal situations, CNS levels of TKI
cannot reach levels known to be therapeutic in peripheral organs. In humans
sunitinib and lapatinib single agent treatment does not decrease the likelihood
of developing brain metastases nor inhibits growth of present brain metastases.
In wild-type mice co-administration of the potent PgP/BCRP inhibitor elacridar
resulted in significantly increased CNS levels, up to 70-80% of the CNS
concentrations established in PgP knock-out mice.
One concern of our novel approach is the possibility of increasing toxicity by
increasing plasma levels of the TKI due to drug efflux pump (PgP/BCRP)
inhibition. In mice plasma levels of sorafenib were not higher in PgP knock-out
mice compared to wild-type mice. However dasatinib and imatinib plasma levels
were 1.5 to 2 times higher in PgP knock-out mice.
An open label phase I healthy volunteer study was performed studying the
pharmacokinetics of a newly developed elacridar formulation. Doses of 25, 250
and 1000 mg were investigated. The 1000 mg dose level (n = 6) resulted in
adequate plasma levels for PgP/BCRP inhibition with minimal side effects.
Recently, a [11C]erlotinib positron emission tomography (PET) tracer has been
developed by dr Hendrikse and Dr. Windhorst of the Department of Nuclear
Medicine & PET Research of the VU Medical Center and used in human subjects. A
complete investigational medicinal product dossier (IMPD) is available. No side
effects were seen in these patients at exposure levels adequate for PET
imaging. The effort to visualize erlotinib uptake -in this study the aim was to
measure uptake in NSCLC tumours and metastases- was successful.
To visualize the penetration of erlotinib through the BBB, [11C]erlotinib PET
scans were performed in mice. Time activity curves demonstrated a faster
transport of [11C]erlotinib out of the brain in wild type mice compared to
mdr1a/1b/Bcrp1 knock out mice. The PET scans showed no [11C]erlotinib uptake in
the brain of PgP/BCRP wild-type mice, and clear uptake of [11C]erlotinib in the
brain of PgP/BCRP knock-out mice.
Until now all data evaluating whether the addition of a PgP/BCRP inhibitor
increases CNS penetration of TKIs has been generated in animal models. This
will be the first in human Proof Of Principle (POC) study. Since about 25-50%
of NSCLC, RCC and Her2 positive breast cancer patients will develop brain
metastases for whom currently effective treatment options are lacking, the need
for an effective treatment strategy to prevent and treat brain metastases in
these patients is crucial.
Study objective
The primary objective of this study is to obtain clinical proof of principle
that the addition of a PgP/BCRP inhibitor increases CNS concentrations of
tyrosine kinase inhibitors by inhibition of drug efflux transporter function in
the blood brain barrier
Study design
Every patient will undergo two PET scans. For both scans an intravenous bolus
of [11C]erlotinib will be administered. For the second scan patients will be
instructed to take 1000 mg elacridar orally. This will enable us to measure the
uptake of [11C]erlotinib in the brain with and without PgP/BCRP inhibition.
Study burden and risks
Radiation burden 2 PET scans (as with normal PET scans)
Infection or bleeding due to arterial sampling trough the a. radialis catheter.
Infection or bleeding due to venous sampling
Nausea, headache, dizziness, altered taste due to the oral intake of 1000 mg
elacridar
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
The study population consists of cancer patients with advanced or metastatic solid tumors for whom no standard therapy is available or for whom a TKI which is a PgP/BCRP substrate is a standard therapeutic option (erlotinib, sunitinib, imatinib, gefitinib, sorafenib, lapatinib, crizotinib, vemurafenib).
Exclusion criteria
Known brain metastases;
Patients who have had previous treatment with central nervous system irradiation;
Treatment with the tyrosine kinase inhibitor used as TKI PET tracer within three half lives before the PET scans;
Patients with known alcoholism, drug addiction and/or psychiatric of physiological condition which in the opinion of the investigator would impair study compliance;.
Patients are not allowed to use co-medication with PgP or BCRP modulators (including OTC medication).
Patients are also not allowed to use co-medication which are PgP or BCRP substrates as this may lead to increased toxicity.
Known hypersensitivity to erlotinib, elacridar or any excipients used in the formulation of either IMPs.
Known contra-indications for a MRI scan.
Design
Recruitment
Medical products/devices used
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 | EUCTR2014-000281-21-NL |
| CCMO | NL47940.031.14 |