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HGG-TCP High Grade Glioma Tumor Concentrations of protein kinase inhibitors


- candidate number19362
- NTR NumberNTR4760
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR28-aug-2014
- Secondary IDs2013.465  VUmc METc
- Public TitleHGG-TCP High Grade Glioma Tumor Concentrations of protein kinase inhibitors
- Scientific TitlePilot study on the determination of tumor concentrations of protein kinase inhibitors in patients with newly diagnosed high-grade glioma
- ACRONYMHGG-TCP
- hypothesisOur hypothesis is that changes in (phospho)proteomic and kinase activity profiles in tissue before and after treatment with PKIs should provide more insight into which differential markers can be clinically used to predict response to this type of targeted therapy. We will investigate the feasibility of obtaining surrogate markers for response prediction provided by comparing kinase activity and (phospho)peptide levels in tumor tissues obtained from study patients (after treatment with PKIs prior to resection) and in tumor tissues obtained from patients in a control group (without treatment with PKIs prior to resection).
- Healt Condition(s) or Problem(s) studiedHigh grade glioma, Angiogenesis
- Inclusion criteria1. Patients without a history of brain tumor
2. Initial brain MR-scan suggesting a high grade glioma, according to the interpretation of an expert neuroradiologist
3. On initial MR-scan a tumor localisation that is deemed resectable without major neurological deficits
4. Patients must have a Karnofsky Performance Score >70%
5. Patients must have a RTOG Neurologic Function Status of 0-2
6. Patients need to have adequate hematological, renal and hepatic function as assessed by the following laboratory requirements to be conducted within seven days prior to start study treatment: - Hemoglobin > 7.0 mmol/l - Absolute neutrophil count (ANC) >1,5 x 10*9/l - Platelet count > 100 x 10*9/l - ALT and AST< 2.5 x ULN - Alkaline phosphatase < 4 x ULN - Serum creatinine eGFR > 50 ml/min
7. Patients are 18 years of older
8. Male and female patients with reproductive potential must use an approved contraceptive method during and for three months after discontinuation of study treatment
9. Patients need to give informed consent
10. Patients should be able to swallow oral medication
- Exclusion criteria1. Patients receiving prior chemotherapy, radiotherapy or anti-angiogenic therapy
2. Use of anti-coagulant therapy
3. Use of CYP3A4 enzyme-inducing drugs, other than dexamethasone (including Carbamazepine, Phenytoine, Phenobarbital)
4. Initial MR-scan of the brain showing tumor hemorrhage or intracerebral hemorrhage
5. Patients with progressive neurological symptoms despite dexamethasone
6. Inability to comply with protocol or study procedures
7. Pregnancy
8. Patients with uncontrolled arterial hypertension. Blood pressure must be <160/95 mmHg at the time of screening on a stable antihypertensive regimen.
9. Patients with a history of cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
10. Patients with evidence or history of bleeding diathesis
11. Patients with a history of venous or arterial thrombo-embolic events or hemorrhagic disease during the past six months
12. Patients with a history of congestive heart failure (NYHA III, IV)
13. Patients with a history of peripheral vascular disease (Fontaine stage III and IV)
14. Patients with stroke or myocardial infarction during the past six months
15. Patients with a history of a recent peptic ulcer disease (endoscopically-proven gastric ulcer, duodenal ulcer of esophageal ulcer) during the past six months
16. Patients with uncontrolled infections (> grade 2 NCI-CTC version 4.0)
- mec approval receivedyes
- multicenter trialno
- randomisedno
- group[default]
- Type2 or more arms, non-randomized
- Studytypeintervention
- planned startdate 1-sep-2014
- planned closingdate1-dec-2017
- Target number of participants15
- InterventionsPatients will be cohort-wise treated with kinase inhibitors for 2 weeks prior to surgery, which is part of standard care. During and at the end of the PKI treatment and during surgery venous bloodsamples will be taken for laboratory analysis. CSF samples will be taken for laboratory analysis during surgery.

Arm1: Drug: Sunitinib
50 mg, once daily, oral use for 14 days

Arm2: Drug: Vandetanib
300 mg, once daily, oral use for 14 days

Arm3: Drug: Erlotinib
150 mg, once daily, oral use for 14 days
- Primary outcomeTo determine PKI and active metabolites concentrations in tumor tissue after approximately two weeks of treatment in patients with a newly diagnosed HGG.
- Secondary outcome1) To determine the correlation of PKI and active metabolites concentrations in tumor with PKI and active metabolites concentrations in plasma- and CSF after approximately two weeks of treatment.
2) To test the feasibility of determining the (phospho)proteomic profiles and kinase activity profiles in tumor tissue and CSF after two weeks of treatment.
3) To determine whether approximately two weeks of treatment with PKIs induces significant difference of the (phospho)proteomic profiles and kinase activities of tumor tissue from study patients and from patients in a control group (without PKI treatment prior to resection).
- TimepointsPatients will be treated for 2 weeks with kinase inhibitors
- Trial web site
- statusplanned
- CONTACT FOR PUBLIC QUERIESProf. dr. H.M.W. Verheul
- CONTACT for SCIENTIFIC QUERIESMD M.E. Linde, van
- Sponsor/Initiator VU University Medical Center
- Funding
(Source(s) of Monetary or Material Support)
Fund = Initiator = Sponsor
- Publications
- Brief summaryIn clinical trials for HGG, multiple agents targeting various oncogenic signaling pathways that play an important role in the biology of HGG have been studied, but unfortunately only a small number of patients seem to benefit from these treatment strategies. Whether these disappointing results are due to a restricted drug delivery through the blood-brain barrier, or due to differential biological characteristics of these HGGs, remains unknown. To better understand these clinical observations and to find potential insight how to overcome them, we intend to measure tumor concentrations of PKIs after approximately two weeks treatment and to determine whether these tumor concentrations correlate with plasma- and CSF concentrations of PKIs. Subsequently, we intend to determine the (phospho)proteomic profiles and kinase inhibitory activity in tumor tissue from these HGG patients after approximately two weeks of treatment with a PKI.
- Main changes (audit trail)
- RECORD28-aug-2014 - 22-sep-2014


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