A Phase I/II Trial of a New Tyrosine Kinase Inhibitor (Tarceva; Erlotinib Hydrochloride; OSI-774) During and After Radiotherapy in the Treatment of Patients With Newly Diagnosed High Grade Glioma and Unfavorable Low-Grade Glioma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 62
- 试验地点
- 3
- 主要终点
- Number of Participants With Dose-limiting Toxicity (DLT)
研究概览
简要总结
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It may also make tumor cells more sensitive to radiation therapy. Giving radiation therapy together with erlotinib may kill more tumor cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of erlotinib when given together with radiation therapy and to see how well they work in treating young patients with newly diagnosed glioma.
详细描述
OBJECTIVES:
Primary
- Determine the maximum tolerated dose and dose-limiting toxicity of erlotinib when administered during and after radiotherapy in young patients with newly diagnosed high-grade glioma and unfavorable low-grade glioma.
- Determine the 1- and 2-year progression-free survival of patients treated with this regimen.
Secondary
- Determine the toxic effects of this regimen in these patients.
- Correlate genetic abnormalities in epidermal growth factor receptor (EGFR) and components of downstream pathways with treatment response in patients treated with this regimen.
- Determine the ability of erlotinib to inhibit EGFR signaling in patients with high-grade glioma who require second surgery.
- Determine the pharmacokinetics of erlotinib and its metabolites in these patients.
- Correlate plasma and cerebrospinal fluid levels of vascular endothelial growth factor and basic fibroblast growth factor with tumor response in patients treated with this regimen.
- Correlate irradiation dosimetry with patterns of failure, standard and investigational imaging, and toxicity in patients treated with this regimen.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Patients with High-Grade/Low-Grade Glioma
Patients with newly diagnosed high-grade glioma (excluding those originating in the brain stem) and unfavorable low-grade glioma who are ≥ 3 years and <26 years of age. Patients receiving enzyme-inducing anticonvulsants (EIACs) are not eligible for this study. Patients with spinal cord tumors will be eligible for the Phase I and Phase II component of this study, but they will not be taken into consideration to estimate PFS in the Phase II component of this trial because of their notoriously worse prognosis. Patients receive erlotinib hydrochloride.
干预措施: Erlotinib hydrochloride (Drug)
结局指标
主要结局
Number of Participants With Dose-limiting Toxicity (DLT)
时间窗: During the first 8 weeks of therapy
DLT was defined as any of the following toxicities attributable to erlotinib therapy: thrombocytopenia grade 3 and 4; neutropenia grade 4; or any grade 3 and 4 non-hematologic toxicity except for grade 3 diarrhea and grade 3 nausea and vomiting lasting ≤48 hours in participants not receiving optimal supportive therapy, grade 3 skin rash, which did not affect normal daily activities, grade 3 fever or nonneutropenic infection, grade 3 seizures, grade 3 weight gain or loss, and grade 3 transaminase elevation that returned to grade 1 or baseline within 7 days. After enrollment of the first 4 participants, grade 3 and 4 electrolyte abnormalities that resolved to ≤grade 2 within 7 days were excluded as DLT. Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0.
Maximum Tolerated Dose (MTD) of Erlotinib
时间窗: During the first 8 weeks of therapy.
MTD was defined as the highest dosage level in which no more than one of six assessable participants experienced dose-limiting toxicities (DLT). The dosage of erlotinib was increased by approximately 30% in each dosage level starting at 80% of the MTD in adults with solid tumors. A traditional 3+3 dose escalation scheme was used to estimate the MTD.
Progression Free Survival (PFS)
时间窗: 1 and 2 years after end of therapy
Progression-free survival (PFS) distributions for the Phase II participants with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were calculated using Kaplan-Meier estimates (n=41). PFS was defined as the interval between treatment start and initial failure, including clinical or radiologic progression or death from any cause. PFS was not calculated for the other disease types.
次要结局
- To Prospectively Investigate the Technical Factors Involved in Planning and Administering Conformal Fractionated RT as Outlined in This Study, and to Correlate RT Dosimetry With Patterns of Failure, Standard and Investigational Imaging and Toxicity(5 Years)
- Cmax of Erlotinib and Its Metabolite OSI-420(After first dose of therapy, and Day 8 of therapy)
- Erlotinib Tmax(After first dose of therapy)
- AUC Time 0-infinite (AUCinf) of Erlotinib and Its Metabolite OSI-420(After first dose of therapy, and Day 8 of therapy)
- Number of Positive Mutations of EGFR and Downstream Pathways(Once at tumor resection and diagnosis)
- Ability of Erlotinib to Inhibit EGFR Signaling(5 Years)
- Correlation Between Standard Magnetic Resonance Imaging and Investigational Radiologic Techniques in Assessing Tumor Response to This Treatment(at diagnosis and regular intervals during therapy (up to 2 years after start of therapy))
- Plasma and CSF Levels of VEGF, bFGF, and SDF1(at diagnosis and regular intervals during therapy (up to 2 years after start of therapy))
- Number of Participants Experiencing Grade 3 or 4 Toxicity Events(From start of therapy through 2 years.)