Clinical trial NCT02239952: HGG-TCP (High Grade Glioma - Tumor Concentrations of Protein Kinase Inhibitors)
Official title: Pilot Study on the Determination of Tumor Concentrations of Protein Kinase Inhibitors in Patients With Newly Diagnosed High-grade Glioma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Cancer
High-grade Glioma
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2014-09-15
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: The purpose of this study is to determine intratumoral concentration of kinase inhibitors upon 2 weeks of treatment in tumor tissue (in the brain) of patients with high-grade gliomas (HGG).

Detailed description: In 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.

Eligibility criteria: Inclusion Criteria:

1. 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 Criteria:

1. 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)

Primary outcomes:
measure: PKI and active metabolites concentrations in tumor tissue
timeFrame: 2 weeks
Secondary outcomes:
measure: Correlation of PKI and active metabolites concentrations in tumor.
timeFrame: 2 weeks
measure: Feasibility of determining the (phospho)proteomic profiles and kinase activity profiles in tumor tissue and CSF.
timeFrame: 2 weeks
measure: Significant difference of the (phospho)proteomic profiles and kinase activities of tumor tissue in study patients and control group.
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
state: Noord-Holland
Study officials:
References:
citation: van Linde ME, Labots M, Brahm CG, Hovinga KE, De Witt Hamer PC, Honeywell RJ, de Goeij-de Haas R, Henneman AA, Knol JC, Peters GJ, Dekker H, Piersma SR, Pham TV, Vandertop WP, Jimenez CR, Verheul HMW. Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma. Clin Cancer Res. 2022 Apr 14;28(8):1595-1602. doi: 10.1158/1078-0432.CCR-21-1933.