Pilot Study on the Determination of Tumor Concentrations of Protein Kinase Inhibitors in Patients With Newly Diagnosed High-grade Glioma
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- PKI and active metabolites concentrations in tumor tissue
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients without a history of brain tumor
- •Initial brain MR-scan suggesting a high grade glioma, according to the interpretation of an expert neuroradiologist
- •On initial MR-scan a tumor localisation that is deemed resectable without major neurological deficits
- •Patients must have a Karnofsky Performance Score ≥ 70%
- •Patients must have a RTOG Neurologic Function Status of 0-2
- •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
- •Patients are 18 years of older
- •Male and female patients with reproductive potential must use an approved contraceptive method during and for three months after discontinuation of study treatment
- •Patients need to give informed consent
- •Patients should be able to swallow oral medication
排除标准
- •Patients receiving prior chemotherapy, radiotherapy or anti-angiogenic therapy
- •Use of anti-coagulant therapy
- •Use of CYP3A4 enzyme-inducing drugs, other than dexamethasone (including Carbamazepine, Phenytoine, Phenobarbital)
- •Initial MR-scan of the brain showing tumor hemorrhage or intracerebral hemorrhage
- •Patients with progressive neurological symptoms despite dexamethasone
- •Inability to comply with protocol or study procedures
- •Patients with uncontrolled arterial hypertension. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen.
- •Patients with a history of cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
- •Patients with evidence or history of bleeding diathesis
- •Patients with a history of venous or arterial thrombo-embolic events or hemorrhagic disease during the past six months
- •Patients with a history of congestive heart failure (NYHA III, IV)
- •Patients with a history of peripheral vascular disease (Fontaine stage III and IV)
- •Patients with stroke or myocardial infarction during the past six months
- •Patients with a history of a recent peptic ulcer disease (endoscopically-proven gastric ulcer, duodenal ulcer of esophageal ulcer) during the past six months
- •Patients with uncontrolled infections (> grade 2 NCI-CTC version 4.0)
研究组 & 干预措施
sunitinib
干预措施: Sunitinib (Drug)
vandetanib
干预措施: vandetanib (Drug)
Erlotinib
干预措施: Erlotinib (Drug)
结局指标
主要结局
PKI and active metabolites concentrations in tumor tissue
时间窗: 2 weeks
PKI concentrations and active metabolites in tumor tissue after approximately two weeks of PKI treatment will be determined.
次要结局
- Significant difference of the (phospho)proteomic profiles and kinase activities of tumor tissue in study patients and control group.(2 weeks)
- Correlation of PKI and active metabolites concentrations in tumor.(2 weeks)
- Feasibility of determining the (phospho)proteomic profiles and kinase activity profiles in tumor tissue and CSF.(2 weeks)
研究者
M.E. van Linde
Medical Oncologist
Amsterdam UMC, location VUmc