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The effect of dexamethasone on the biodistribution of [3-N-11C]temozolomide in glioblastoma multiforme patients.


- candidate number13433
- NTR NumberNTR3662
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR11-okt-2012
- Secondary IDs2012-13 / NL38760.029.11; METC Vumc / CCMO
- Public TitleThe effect of dexamethasone on the biodistribution of [3-N-11C]temozolomide in glioblastoma multiforme patients.
- Scientific TitleThe effect of dexamethasone on the biodistribution of [3-N-11C]temozolomide in glioblastoma multiforme patients: A pilot study.
- ACRONYMEffect of dexamethasone on the biodistribution of [11C]temozolomide
- hypothesisInteraction between temozolomide and dexamethasone at the P-gp level may affect temozolomide concentration in the brain and in glioma tissue, which may hamper its efficacy.
- Healt Condition(s) or Problem(s) studiedTemozolomide, Glioblastoma multiforme, Biodistribution, Dexamethasone
- Inclusion criteria1. Histopathological confirmed diagnosis of GBM;
2. Remainder of tumor on post-(chemo)irradiation follow-up MRI; this remainder of tumor must be at least 5 mm in diameter;
3. Age between 18-70 years;
4. Performance status Karnofsky index > 60;
5. Laboratory requirements:
A. Platelets > 100 x 109/l;
B. Hb must be >8 mmol \ litre at the time of the screening for males and >7.5mmol \ litre for females;
C. Neutrophils > 1.5 x 109/L;
D. Liver- and kidney function: serum creatinine level < 1.5 times the upper limit of normal, liver function values <3 times the upper limit of normal.
6. All subjects have to be willing and able to give informed consent;
7. Written informed consent of each subject;
8. No use of DXM (at time of participation to this study).
- Exclusion criteria1. Any clinical significant abnormality of any clinical laboratory test, with the exception of the values mentioned above (for platelets, haemoglobin, neutrophils, kidney- and liver function);
2. Any subject who has received any investigational medication within 30 days prior to the start of this study, or who is scheduled to receive an investigational drug;
3. Major psychiatric or neurological disorder other than GBM with or without epilepsy;
4. History of alcohol and/or drug abuse (DSM-IV criteria);
5. History of coagulation problems;
6. Claustrophobia;
7. Abnormalities on MRI other than GBM and/or abnormalities on MRI other than white matter changes or an incidental small lacunar lesion without clinical diagnosis;
8. Metal objects in or around the body (braces, pacemaker, metal fragments);
9. Use of antithrombotics or ASA;
10. Use of drugs that are known to be P-gp substrates, other than AEDs;
11. Need for elective surgery ≤ 6 weeks;
12. Pregnancy or nursing mothers;
13. Unable to understand or read the Dutch language;
14. Any of the following contra-indication for DXM (see also SPC of DXM):
A. Hypersensitivity to one of the active constituents or additives;
B. Ulcus ventriculi or ulcus duodeni;
C. Active infections: viral infections, systemic fungal infections, parasitic infections, tropical worm infections;
D. Recent vaccination with living weakened virus;
E. Anamnestic hypersensibility for sulphite;
F. History of glucocorticoid-induced myopathy;
G. Diabetes mellitus (type 1 or 2).
- mec approval receivedyes
- multicenter trialno
- randomisedno
- groupParallel
- TypeSingle arm
- Studytypeintervention
- planned startdate 8-okt-2012
- planned closingdate8-okt-2014
- Target number of participants12
- InterventionsPatients will be PET-scanned twice (twice the combination of a [15O] H2O - and a [11C]temozolomide PET scan) on one day. One gift of 10 mg dexamethasone intravenously will be given between the morning and and afternoon scanning sessions.
- Primary outcomeDetermination of the effect of dexamethasone on the biodistribution of [3-N-11C-methyl]temozolomide in GBM patients during the adjuvant phase of chemotherapy.
- Secondary outcome1. To assess plasma kinetics of [11C]temozolomide in humans, including assessment of the presence of radioactive metabolites;
2. To study the effect of DXM on CBF;
3. If there is an effect of DXM on CBF, we will study the relation between changes in CBF and [11C]temozolomide uptake in the brain and especially in the brain tumour.
- Timepoints1. One timepoint measurement;
2. Two scans (combination of a [15O] H2O - and a [11C]temozolomide PET scan) on one day, in the morning and in the afternoon.
- Trial web siteN/A
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESMD E.A.M. Froklage
- CONTACT for SCIENTIFIC QUERIESMD, PhD J.C. Reijneveld
- Sponsor/Initiator VU University Medical Center
- Funding
(Source(s) of Monetary or Material Support)
VU University Medical Center
- PublicationsN/A
- Brief summaryRadiotherapy and temozolomide (TMZ) are expected to be the backbone of treatment for patients with glioblastoma multiforme (GBM), and possibly also for patients with other glioma subtypes, during the next decade(s). Apart from (chemo-)irradiation and adjuvant courses of TMZ, the majority of glioma patients are treated with corticosteroids in order to avoid peritumoral edema, and approximately half of the patients are on anti-epileptic drugs (AED), such as levetiracetam. Although interactions with other drugs are suspected to affect the efficacy of TMZ, hardly any quantitative data on this issue are available. Corticosteroids, such as DXM, are thought to affect the levels of other drugs in the brain, including TMZ, for example by causing a dramatic decrease in blood-tumor barrier permeability. Secondly, DXM influences transcellular and paracellular pathways that regulate transport of drugs over the blood-brain tumor barrier. Thirdly, DXM increases P-glycoprotein- (P-gp) and breast cancer resistance associated protein (BCRP)-mediated drug efflux activity in the blood-brain barrier (BBB). A variety of cytostatic agents and many AEDs are substrates for P-gp. Thus, interactions between TMZ, corticosteroids and AEDs at the P-gp level may affect TMZ concentration in the brain and in glioma tumor tissue, which may hamper its efficacy. Increased knowledge on the biodistribution of TMZ will improve treatment by allowing to adjust TMZ dosage when, for example, corticosteroids are prescribed. Positron Emission Tomography (PET) offers an excellent opportunity to determine biodistribution and pharmacokinetics of drugs such as TMZ, and for that reason, PET is the ideal instrument to quantify the effects of co-medication, e.g. DXM. Previous studies have demonstrated that PET-scanning of [3-N-11C-methyl]temozolomide ([11C]TMZ) is a robust tool to analyse and predict tissue drug concentrations in order to determine the most rational dosing schedules of TMZ. When we will be able to visualize and quantify the effects of corticosteroids on [11C]TMZ kinetics in GBM, this may contribute to the optimalization of treatment schedules. Furthermore, it is also important to assess the effect of DXM on the cerebral blood flow (CBF), as studies on the effect of DXM on CBF have, so far, been inconclusive. One study demonstrated that DXM decreases the CBF. In contrast, two other studies have been shown that DXM did not significantly alter CBF. However, two of these three studies have evaluated the effect of DXM on CBF more than 12 hours after DXM. In fact, the only study that did assess this effect already after 1-6 hours, found that DXM did not significantly alter CBF. As present study will evaluate the effect of DXM on [11C]TMZ kinetics in GBM approximately 160 minutes after a single gift of DXM, the possible effect of DXM on CBF has to be taken into account to assess whether an alteration in CBF (e.g. a reduction) attributes to an alteration in [11C]TMZ biodistribution and kinetics, or not. This possible effect of DXM on CBF will be evaluated by means of [15O]H2O PET scans before and after a single gift of DXM.In summary, this pilot study will primary focus on the effect of DXM on the biodistribution and pharmacokinetics of [11C]TMZ in GBM patients during the adjuvant phase of their treatment. Secondly, the effect of DXM on CBF will be evaluated.
- Main changes (audit trail)
- RECORD11-okt-2012 - 22-okt-2012


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