A Phase I Study of Intracranially Administered Carboxylesterase-Expressing Neural Stem Cells in Combination With Intravenous Irinotecan in Patients With Recurrent High-Grade Gliomas
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 18
- 试验地点
- 2
- 主要终点
- Number of Participants With Grade 3 or Higher Toxicity Profile Attributed to Irinotecan
研究概览
简要总结
This phase I trial studies the side effects and best dose of carboxylesterase-expressing allogeneic neural stem cells when given together with irinotecan hydrochloride in treating patients with high-grade gliomas that have come back. Placing genetically modified neural stem cells into brain tumor cells may make the tumor more sensitive to irinotecan hydrochloride. Irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving carboxylesterase-expressing allogeneic neural stem cells and irinotecan hydrochloride may be a better treatment for high-grade gliomas.
详细描述
PRIMARY OBJECTIVE:
I. To define the recommended phase II doses (RP2D) of intracranially administered carboxylesterase-expressing allogeneic neural stem cells (hCE1m6-NSCs) in combination with intravenous irinotecan in patients with recurrent high grade glioma.
SECONDARY OBJECTIVES:
I. To describe the relationship between hCE1m6-NSC dose and SN-38 (SN-38) concentrations in brain interstitium.
II. To characterize the relationship between intracerebral and systemic concentrations of irinotecan (irinotecan hydrochloride) and SN-38.
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 69 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient must be able to understand and be willing to sign a written informed consent document
- •Participant must be willing to comply with study and/or follow-up procedures
- •Karnofsky performance status >= 70%
- •Life expectancy of >= 3 months
- •Histologically-confirmed diagnosis of a grade III or IV glioma (including glioblastoma, 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 tumor(s); if a patient is going to be enrolled to dose level two or higher, the patient must have a component of supratentorial disease (so as to enable placement of a Rickham reservoir/catheter) that is amenable to resection or biopsy
- •High-grade glioma has recurred or progressed after prior treatment with brain radiation and temozolomide
- •Participant 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 judgment, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles
- •Neurosurgeon finds the prospective participant is able to undergo neurosurgery
- •Any number of prior therapies is permitted; from the start of study treatment, the following time periods must have elapsed: 6 weeks from nitrosourea-containing chemotherapy, 4 weeks from non-nitrosourea-containing cytotoxic chemotherapy (except 23 days from last daily dose of temozolomide taken in a 5 of 28 day regimen), and 2 weeks from last dose of a targeted agent (except 4 weeks for bevacizumab); there is no time period requirement for prior radiation therapy
- •Any clinically significant toxicity from prior therapy must have improved to grade 0 or grade 1
- •Absolute neutrophil count (ANC) >= 1,500 cells/ul
- •Platelets > 100,000 cells/ul
- •Total bilirubin =< 2.0 mg/dl
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 4 times institutional upper limit of normal
- •Serum creatinine =< 1.5 x the institutional upper limit of normal
- •Homozygous negative for the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT 1A1)*28 allele
- •Absence anti-human leukocyte antigen (HLA) antibodies specific for HLA class I antigens expressed by the coagulation factor III (thromboplastin, tissue factor) (F3).cytosine deaminase (CD).carboxylesterase (CE) NSCs
- •Negative serum pregnancy test (women of childbearing potential only)
- •Agreement by females of childbearing potential and sexually active males 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
排除标准
- •Prior therapy with neural stem cells
- •Use of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers including hepatic enzyme-inducing anticonvulsants (phenytoin, fosphenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine) within 2 weeks prior to start of study treatment
- •Use of moderate to strong CYP3A4 inhibitors within 2 weeks prior to start of study treatment
- •Use of drugs known to inhibit UGT1A1, such as atazanir, gemfibrozil, indinavir, or ketoconazole, within 2 weeks prior to start of study treatment
- •Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids, such as systemic cyclosporine and tacrolimus; consult principal investigator for questions, including necessary washout period for the specific drug
- •Flucytosine within 2 weeks prior to start of study treatment
- •Use of herbal medications
- •Current use (or planned use during the treatment period) of other investigational agents, or biological, chemotherapy, radiation or other anti-tumor therapy
- •Patient has known human immunodeficiency virus (HIV) or hepatitis C infection; baseline testing for HIV or hepatitis C is not required
- •Prospective participant is unable to undergo a magnetic resonance imaging (MRI) with contrast agent
- •Known chronic or active viral infections of the central nervous system (CNS)
- •Clinically significant uncontrolled illness
- •Active infection requiring antibiotics
- •Diagnosis of Gilbert?s disease
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan
- •Known sensitivity to any of the products to be administered during dosing
- •Any other active malignancy
- •Pregnant women and women who are lactating
- •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
- •Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
研究组 & 干预措施
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)
Patients receive carboxylesterase-expressing allogeneic neural stem cells intracranially over 1.5-4.5 hours on days 1 and 15 (day 1 only for patients at dose level 1) and irinotecan hydrochloride IV over 90 minutes on days 3 and 17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Carboxylesterase-expressing Allogeneic Neural Stem Cells (Biological)
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)
Patients receive carboxylesterase-expressing allogeneic neural stem cells intracranially over 1.5-4.5 hours on days 1 and 15 (day 1 only for patients at dose level 1) and irinotecan hydrochloride IV over 90 minutes on days 3 and 17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)
Patients receive carboxylesterase-expressing allogeneic neural stem cells intracranially over 1.5-4.5 hours on days 1 and 15 (day 1 only for patients at dose level 1) and irinotecan hydrochloride IV over 90 minutes on days 3 and 17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)
Patients receive carboxylesterase-expressing allogeneic neural stem cells intracranially over 1.5-4.5 hours on days 1 and 15 (day 1 only for patients at dose level 1) and irinotecan hydrochloride IV over 90 minutes on days 3 and 17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Irinotecan (Drug)
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)
Patients receive carboxylesterase-expressing allogeneic neural stem cells intracranially over 1.5-4.5 hours on days 1 and 15 (day 1 only for patients at dose level 1) and irinotecan hydrochloride IV over 90 minutes on days 3 and 17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Irinotecan Hydrochloride (Drug)
结局指标
主要结局
Number of Participants With Grade 3 or Higher Toxicity Profile Attributed to Irinotecan
时间窗: Followed 30 days post treatment for all toxicities (min=33,max 142 days), up to 5 years for gene therapy toxicities
Grade 3 or higher toxicity profile as assessed by the NCI CTCAE version version 4.0. Toxicities reported are possibly, probably or definitely related to Irinotecan.
Number of Participants Experiencing a Dose-limiting Toxicity (DLT)
时间窗: 28 days post first dose of NSC treatment on day 1, cycle 1
Toxicities will be graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. A DLT is defined as an adverse event that is related to the administration of NSCs and/or irinotecan, occurs during the first treatment cycle and meets any of the following: 1. Received less than 80% of study treatments except due to CNS toxicity 2. Grade 4 thrombocytopenia or anemia or neutropenia lasting \> 7 days 3. Febrile neutropenia with ANC \< 0.5 x10\^9/L 4. Grade 3 central nervous system (CNS) disorder lasting \> 7 days not attributed to tumor or surgery and not present at baseline 5. Second occurrence of grade 3 CNS disorder not attributed to tumor or surgery and not present at baseline 6. Any grade 4 CNS disorder not attributed to tumor or surgery and not present at baseline 7. Grade 3 toxicity despite therapy lasting \> 7 days 8. Grade 3 toxicity resulting in study agent discontinuation 9. Grade 4 toxicity, except grade 4 diarrhea responding to therapy within 3 days
Number of Participants With Grade 3 or Higher Toxicity Profile Attributed to NSCs
时间窗: Followed 30 days post treatment for all toxicities (min=33,max 142 days), up to 5 years for gene therapy toxicities
Grade 3 or higher toxicity profile as assessed by the NCI CTCAE version version 4.0. Toxicities reported are possibly, probably or definitely related to NSCs.
次要结局
- Median Ratio of SN-38 Area Under the Curve (AUC) to CPT-11 AUC in Plasma(Pre-dose, at 90 minutes (just prior to the end of the infusion), and then at 30 minutes, 1, 2, 4, 8, 24, and 48 hours after the end of the infusion after day 1, cycle 1)
- Median Ratio of SN-38 AUC to CPT-11 AUC in the Brain(Pre-dose, at 90 minutes (just prior to the end of the infusion), and then at 30 minutes, 1, 2, 4, 8, 24, and 48 hours after the end of the infusion after day 1, cycle 1)
- Number of Participants With Clinical Benefit Defined by Response Assessment in Neuro-Oncology (RANO)(Until death or disease progression, a median of 2 months, up to 6 months)