06-benzylguanine (BG) and Temozolomide (TMZ) Therapy of Glioblastoma Multiforme (GBM) in Patients With MGMT Positive Tumors With Infusion of Autologous P140KMGMT+ Hematopoietic Progenitors to Protect Hematopoiesis

Stanton Gerson MD1 个研究点分布在 1 个国家目标入组 10 人开始时间: 2011年11月22日最近更新: 2023年3月2日

适应症

干预措施

试验速览

阶段: 1 期
状态: 已完成
发起方
入组人数: 10
试验地点: 1
主要终点: Feasibility and safety of infusing autologous P140K MGMT-transduced hematopoietic progenitors into patients with GBM

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. O6-benzylguanine may help temozolomide work better by making tumor cells more sensitive to the drug. Giving genetically modified peripheral blood stem cells during or after treatment may prevent side effects caused by chemotherapy.

PURPOSE: This clinical trial studies O6-benzylguanine and temozolomide in combination with genetically modified peripheral blood stem cells in treating patients with newly diagnosed glioblastoma multiforme.

详细描述

OBJECTIVES:

Primary

To evaluate the feasibility of introducing and expressing P140K MGMT cDNA from a lentiviral-based provirus in autologous hematopoietic stem cells harvested from Glioblastoma multiforme (GBM) patients.
To assess the safety associated with infusion of autologous hematopoietic stem cells transduced ex vivo with a lentiviral vector expressing P140K MGMT in patients with GBM.

Secondary

To determine whether any patients who receive P140K MGMT-transduced CD34 cells tolerate O6-benzylguanine (BG) and dose-escalated temozolomide (TMZ) without myelosuppression.
To evaluate the ability to detect P140K-transduced BG and TMZ-resistant hematopoietic cells from the bone marrow and peripheral blood in patients infused with P140K-transduced CD34 progenitors.
To evaluate the feasibility of in vivo enrichment of P140K-expressing hematopoietic cells by repeated treatments of BG and TMZ at doses that appear therapeutic for GBM.
To evaluate the efficacy of various types of chemotherapy with or without radiotherapy on conditioning the patient's bone marrow to host the transduced autologous hematopoetic stem cells.
To evaluate tumor response, progression-free survival, and overall survival.

研究设计

研究类型: Interventional
分配方式: Non Randomized
干预模型: Parallel
主要目的: Treatment
盲法: None

入排标准

年龄范围: 18 Years 至 70 Years（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•Patients with histologically confirmed, newly diagnosed, supratentorial GBM who have undergone gross total tumor resections or near gross total resection (resection of >90% of enhancing tumor demonstrated by MRI) are eligible up to their third post-operative week. Patients with infratentorial disease, multifocal or leptomeningeal disease will be excluded. In general, patients will not have > 1 cm residual measurable or evaluable disease after surgical tumor resection.
•ECOG performance status 0-2 or Karnofsky ≥
•Patients must have received no myelosuppressive chemotherapy prior to the diagnosis of GBM.
•Life expectancy of at least 12 weeks.
•Adequate hematologic (ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, Hgb ≥ 9.5) , hepatic (Bilirubin ≤ 2.0 mg/dl, AST and ALT less than or equal to 3 times upper limit of normal, prothrombin time <1.2 times normal), and renal (Serum creatinine ≤ 2.0 mg/dl or Creatinine Clearance ≥ 60mL/min/1.73 m2 for subjects with serum creatinine levels above institutional normal) . These tests will be repeated within 2 weeks of treatment with BG and TMZ, and must meet the same criteria.
•EKG without evidence of acute cardiac disease.
•Left ventricular ejection fraction (LVEF) ≥ 40
•Post-operative steroids are tapered to ≤ 24 mg decadron/d
•Patients of child-bearing potential must be using single barrier contraception
•Willingness and ability to provide informed consent.
•Patient must have all sutures removed prior to registration
•Patient must be considered to be clinically stable.
•Exclusion criteria:
•Medical condition associated with immunosuppression, active infection or medical illness which may jeopardize patient safety.
•HIV seropositivity. This exclusion is included for two reasons. First, there is evidence of decreased marrow reserve in HIV+ patients and antiviral treatment is associated with myelosuppression. Thus, drug treatment designed to be myelosuppressive may be more toxic in this patient population. Second, extensive laboratory culturing of the bone marrow and peripheral blood progenitor cells is required. No preclinical samples which are HIV+ have been evaluated with the gene transfer modality proposed and thus the feasibility and safety of gene transfer and selection in HIV+ samples cannot yet be advocated. Such studies are planned so as to not preclude HIV+ patients in later studies.
•Pregnant or lactating women. There is data to indicate that TMZ is teratogenic and carcinogenic. Thus, its use in pregnant women would confer unnecessary risk to the fetus.
•Patients with symptomatic pulmonary disease and other severe co-morbid conditions
•Patients with cardiac insufficiency and an LVEF of < 40%. History of acute coronary event disease or arrhythmia within 6 months prior to enrollment
•Prior chemotherapy (including gliadel wafers) or hematopoietic cell transplantation.
•Inability to undergo repeated MRI evaluation.
•Prior diagnosis of malignant disease within a three year period with the exception of surgically cured basal cell carcinoma or carcinoma in situ of the cervix
•Mental incapacity or psychiatric illness preventing informed consent

排除标准

未提供

研究组 & 干预措施

Cohort 2

Active Comparator

LV gene transfer prior to concurrent chemo-radiotherapy

干预措施: radiation therapy (Radiation)

Cohort 2

Active Comparator

LV gene transfer prior to concurrent chemo-radiotherapy

干预措施: in vitro-treated peripheral blood stem cell transplantation (Procedure)

Cohort 2

Active Comparator

LV gene transfer prior to concurrent chemo-radiotherapy

干预措施: O6-benzylguanine (Drug)

Cohort 2

Active Comparator

LV gene transfer prior to concurrent chemo-radiotherapy

干预措施: temozolomide (Drug)

Cohort 2

Active Comparator

LV gene transfer prior to concurrent chemo-radiotherapy

干预措施: laboratory biomarker analysis (Other)

Cohort 2

Active Comparator

LV gene transfer prior to concurrent chemo-radiotherapy

干预措施: autologous hematopoietic stem cell transplantation (Procedure)