A Phase I Study of Cytosine Deaminase-Expressing Neural Stem Cells in Combination With Oral 5-Fluorocytosine and Leucovorin for the Treatment of Recurrent High-Grade Gliomas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)
研究概览
简要总结
This phase I trial studies the side effects and determines the best dose of genetically modified neural stem cells and flucytosine when given together with leucovorin for treating patients with recurrent high-grade gliomas. Neural stem cells can travel to sites of tumor in the brain. The neural stem cells that are being used in this study were genetically modified express the enzyme cytosine deaminase (CD), which converts the prodrug flucytosine (5-FC) into the chemotherapy agent 5-fluorouracil (5-FU). Leucovorin may help 5-FU kill more tumor cells. The CD-expressing neural stem cells are administered directly into the brain. After giving the neural stem cells a few days to spread out and migrate to tumor cells, research participants take a 7 day course of oral 5-FC. (Depending on when a research participant enters the study, they may also be given leucovorin to take with the 5-FC.) When the 5-FC crosses into brain, the neural stem cells convert it into 5-FU, which diffuses out of the neural stem cells to preferentially kill rapidly dividing tumor cells while minimizing toxicity to healthy tissues. A Rickham catheter, placed at the time of surgery, will be used to administer additional doses of NSCs every two weeks, followed each time by a 7 day course of oral 5-FC (and possibly leucovorin). This neural stem cell-based anti-cancer strategy may be an effective treatment for high-grade gliomas.
Funding Source - FDA OOPD
详细描述
PRIMARY OBJECTIVES:
I. To define the phase II recommended dose of intracerebrally administered cytosine deaminase (CD)-expressing neural stem cells (NSCs) in combination with oral 5-fluorocytosine (FC) (flucytosine) and leucovorin.
II. To determine the feasibility of treating study patients with more than 1 dose of NSCs followed by 7-day courses of 5-FC and leucovorin.
SECONDARY OBJECTIVES:
I. To assess for possible development of NSC immunogenicity (anti-NSC T cell and/or antibody response) with repeat doses of NSCs.
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
- •Patient has had a prior, histologically-confirmed, diagnosis of a grade III or IV glioma (including glioblastoma, anaplastic oligodendroglioma, or anaplastic astrocytoma, gliosarcoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma), or has a prior, histologically-confirmed, diagnosis of a grade II glioma and now has radiographic findings consistent with a high-grade glioma (grade III or IV)
- •Imaging studies show evidence of recurrent, supratentorial tumor(s). The presence of infratentorial tumor is allowed as long as the patient also has supratentorial disease that is amenable to resection or biopsy.
- •Patient's high-grade glioma has recurred or progressed after prior treatment with brain radiation and temozolomide
- •Patient has a Karnofsky performance status of >= 70%
- •Patient has a life expectancy of >= 3 months
- •Female patients of childbearing potential and sexually-active male patients must agree to use an effective method of contraception while participating in this study; women of childbearing potential must have a negative pregnancy test =< 2 weeks prior to registration
- •The patient must be in need of a craniotomy for tumor resection or a stereotactic brain biopsy for the purpose of diagnosis or differentiating between tumor progression versus treatment-induced effects following radiation therapy +/- chemotherapy
- •Based on the neurosurgeon's judgement, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles
- •Absolute neutrophil count (ANC) >= 1500 cells/mm^3
- •Platelet count >= 100,000 cells/mm^3
- •Total bilirubin =< 2.0 mg/dl
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 4 times the institutional upper limit of normal
- •Serum creatinine =< the institutional upper limit of normal
- •There is no limit to the number of prior therapies
- •All subjects must have the ability to understand and the willingness to sign a written informed consent
排除标准
- •Patient has anti-human leukocyte antigen (HLA) antibodies specific for HLA antigens expressed by the NSCs
- •Patient has not recovered from any toxicity of prior therapies; an interval of
- •At least 6 weeks must have elapsed since taking a nitrosourea-containing chemotherapy regimen
- •At least 4 weeks since completing a non-nitrosourea-containing cytotoxic chemotherapy regimen (except temozolomide: only an interval of 23 days is required from the last dose administered when patient has been recently treated with the standard temozolomide regimen of daily for 5 days, repeated every 28 days)
- •At least 2 weeks from taking the last dose of targeted agent
- •At least 4 weeks from the last dose of bevacizumab
- •Patient is unable to undergo a magnetic resonance imaging (MRI)
- •Patient is allergic to 5-FC, leucovorin, or 5-FU
- •Patient has chronic or active viral infections of the central nervous system (CNS)
- •Patient has a coagulopathy or bleeding disorder
- •Patient has an uncontrolled illness including ongoing or active infection
- •Patient is receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
- •Patient has had prior therapy with neural stem cells
- •Patient is pregnant or breast feeding; pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is participating in this study
- •Patient has another active malignancy
- •Non-compliance; a patient has a serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the safety monitoring requirements and completion of treatment according to this protocol
研究组 & 干预措施
Treatment (neural stem cells, flucytosine, leucovorin)
Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, they may also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Dose escalation used the following dose levels:
Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)
Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)
Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)
Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
干预措施: E. coli CD-expressing genetically modified neural stem cells (Biological)
Treatment (neural stem cells, flucytosine, leucovorin)
Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, they may also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Dose escalation used the following dose levels:
Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)
Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)
Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)
Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
干预措施: flucytosine (Drug)
Treatment (neural stem cells, flucytosine, leucovorin)
Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, they may also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Dose escalation used the following dose levels:
Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)
Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)
Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)
Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
干预措施: leucovorin calcium (Drug)
Treatment (neural stem cells, flucytosine, leucovorin)
Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, they may also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Dose escalation used the following dose levels:
Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)
Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)
Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)
Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
干预措施: pharmacological study (Other)
Treatment (neural stem cells, flucytosine, leucovorin)
Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, they may also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Dose escalation used the following dose levels:
Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)
Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)
Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)
Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)
时间窗: Day 28 of course 1
Number of DLTs per dose level and the MTD/MFD.
Number of Participants With Mechanical Issues With Repeat Administrations of NSCs Via Rickham
时间窗: 28 days after last infusion of NSCs, up to 6 months total
Number of participants with mechanical issues with repeat administrations of NSCs via Rickham.
次要结局
- Number of Participants Developing Antibodies Against NSCs(While receiving treatment, up to 6 months.)
- Average Steady State Levels of 5-FC Concentrations in Plasma(Samples were obtained prior to the first dose of 5-FC then every 30 minutes for 3 hours, additional samples at 4 and 6 hours after the morning doses on days 4, 5. On days 6, 7, 8 blood samples were collected just before morning dose and 90 minutes later)
- Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria(Up to 3 years post NSC infusion)
- Average Steady State Levels of 5-FC and 5-FU in the Brain(Following the first dose of 5-FC, samples were collected every hour for 24 hours and then every 3 hours thereafter until the end of the 7-day course of 5-FC or until the microdialysis catheter stopped functioning.)
- Comparison of 5-FC in the Brain to 5-FC in the Plasma(The ratio of average brain interstitial 5-FC and 5-FU concentrations to average plasma steady-state levels was calculated using all measured data.)