Chronic Convection Enhanced Delivery of Topotecan for Recurrent High Grade Gliomas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Dose at which all patients have had no greater than grade 2 adverse reactions
研究概览
简要总结
The primary goal of this study is to establish, for the first time, safety of prolonged intracerebral convection enhanced delivery of chemotherapy in patients with recurrent high grade glioma (HGG). Secondary objectives will include determination of topotecan (TPT) distribution and radiographic tumor response with prolonged continuous intracerebral convection-enhanced delivery (CED).
详细描述
Malignant gliomas are among the most pernicious of human tumors - locally invasive and universally recurrent, with recurrence usually occurring within two centimeters of the original resection cavity. Although numerous chemotherapeutic drugs demonstrate significant anti-tumor activity in preclinical studies, the efficacy in clinical trials has been dismal because systemic delivery fails to achieve therapeutic drug levels in tumor cells due to various factors including limited blood-brain barrier permeability and systemic toxicity.
Convection-enhanced delivery (CED) is a method of regional drug delivery that circumvents this problem. Phase 1 clinical trial has shown that a potent topoisomerase inhibitor, topotecan (TPT), can be safely and effectively delivered by CED into patients with recurrent malignant gliomas. This study will expand on these clinical results to address two current limitations to the clinical application of CED: 1) A reliable method for non-invasively monitoring drug distribution throughout the tumor and brain does not exist; and 2) Duration of CED therapy has been limited to short-term infusions secondary to the use of externalized infusion pumps.
The hypothesis is that extended chronic local-regional delivery of TPT is safe, effective and feasible in patients with recurrent gliomas. TPT will be directly and chronically delivered into the tumor and surrounding brain by CED through subcutaneously implanted pumps while innovating a methodology for monitoring the drug distribution through non-invasive imaging. This strategy will overcome the limitations of chemotherapy as currently used in the treatment of gliomas, and may be applicable to other central nervous system (CNS) diseases currently limited by drug delivery barriers.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have a recurrent malignant glioma (World Health Organization (WHO) grade III-IV), including recurrent glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, and anaplastic ependymoma. Stereotactic biopsies will be performed to confirm this diagnosis prior to initiating the treatment.
- •Patients with tumors of the brain must have been previously treated with surgical resection, external beam radiation, and temozolomide chemotherapy.
- •An magnetic resonance (MR) scan must be obtained within 30 days of enrollment and must demonstrate an enhancing mass without significant mass effect. Tumors must be less than 32 cc in total volume. The lesion must be stereotactically accessible.
- •Patients must have demonstrated evidence of increasing contrast enhancement on MR or computed tomography (CT) imaging while on stable or increasing dose of steroid.
- •Karnofsky performance score of greater than or equal to
- •Men and women of childbearing potential must practice birth control. Women of child bearing potential must have a urine pregnancy test within 7 days of study entry.
- •Patients must possess the ability to give Informed Consent.
- •Patients must be willing to and medically capable of undergoing the surgical operation.
- •There is no upper age limit. Patients at extreme upper end of the age spectrum will not be automatically excluded, but will be carefully scrutinized to determine their suitability for this procedure.
- •Patients must be at least 18 years old.
- •Patients must have normal organ and marrow function as defined below:
- •Leukocytes: ≥3,000/ cells per microliter of blood (mcL)
- •Absolute neutrophil count: ≥1,500/mcL
- •Platelets: ≥100,000/mcL
- •Total bilirubin: within normal institutional limits
- •aspartate aminotransferase (AST) (SGOT)/alanine aminotransferase (ALT) (SGPT): ≤2.5 × institutional upper limit of normal
- •Creatinine: within normal institutional limits OR
- •Creatinine clearance: ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
排除标准
- •Patients with diffuse subependymal or cerebral spinal fluid (CSF) disease.
- •Patients with tumors involving the cerebellum or both cerebral hemispheres.
- •Patients with an active infection requiring treatment or having an unexplained febrile illness.
- •Patients who are known HIV, Hepatitis B or Hepatitis C positive. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with topotecan. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
- •Patients with systemic diseases which may be associated with unacceptable anesthetic/operative risk.
- •Patients who have previously received systemic topotecan for their tumor
- •Patients who are not able to receive an MRI scan.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to topotecan, other topoisomerase inhibitors or gadolinium compounds.
研究组 & 干预措施
Long term CED of Topotecan
An additional 5 patients will be treated with TPT by CED maintained for 32 days. TPT infusions will be carried out for 32 days using Synchromed II infusion pumps with the same infusion parameters and experimental conditions used in the short term studies.
干预措施: Synchromed II infusion pumps (Device)
Long term CED of Topotecan
An additional 5 patients will be treated with TPT by CED maintained for 32 days. TPT infusions will be carried out for 32 days using Synchromed II infusion pumps with the same infusion parameters and experimental conditions used in the short term studies.
干预措施: Topotecan (Drug)
Long term CED of Topotecan
An additional 5 patients will be treated with TPT by CED maintained for 32 days. TPT infusions will be carried out for 32 days using Synchromed II infusion pumps with the same infusion parameters and experimental conditions used in the short term studies.
干预措施: Gadolinium (Drug)
结局指标
主要结局
Dose at which all patients have had no greater than grade 2 adverse reactions
时间窗: Up to 29 days
This is designed to measure the safety of prolonged intracerebral convection enhanced delivery of chemotherapy in patients.
次要结局
- Change in radiographic tumor response(Baseline, 6 weeks post-treatment)
- Clinical toxicity rate(Up to 29 days)
- Progression free survival (PFS)(Every 3-6 months, up to 5 years)
研究者
Jeffrey N. Bruce
Edgar M. Housepian Professor of Neurological Surgery Research at, Dept of Neurological Surgery
Columbia University