A Clinical Trial of Gene-Modified Stem Cells to Generate HIV-Resistant Cells in Conjunction With Standard Chemotherapy for Treatment of Lymphoma in Patients With HIV Infection
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Feasibility of collection: defined as collection of >= 4.0 x 10^6 CD34+ cells/kg for genetic modification
研究概览
简要总结
This pilot phase I trial studies the side effects and best dose of human immunodeficiency virus (HIV)-resistant gene modified stem cells in treating HIV-positive patients who are undergoing first-line treatment for Hodgkin or Non-Hodgkin Lymphoma. Stem cells are collected from the patient and HIV-resistance genes are placed into the stem cells. The stem cells are then re-infused into the patient. These genetically modified stem cells may help the body make cells that are resistant to HIV infection.
详细描述
PRIMARY OBJECTIVES:
I. To determine the safety and feasibility of infusing C46/CCR5/P140K lentiviral vector-transduced autologous hematopoietic stem progenitor cells (HSPC) (gene modified, HIV-protected HSPC) after standard first line treatment of lymphoma in patients with HIV infection.
II. To determine the dose of carmustine (BCNU) in combination with O6-benzylguanine (O6BG) that results in selection in vivo of gene-modified HIV resistant cells with minimal toxicity.
III. To estimate the effect of HIV infection on the presence of HIV-resistant blood cells as measured by genetic marking for vector sequences before and after highly active antiretroviral therapy (HAART) interruption.
SECONDARY OBJECTIVES:
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 66 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HIV-1 seropositive
- •Stable, continuous antiretroviral treatment, defined as a multi-drug regimen (excluding zidovudine, also known as azidothymidine [AZT], Retrovir) prior to enrollment, as demonstrated by HIV plasma viral load < 50 copies/mL
- •Previously untreated non-Hodgkin lymphoma or Hodgkin lymphoma; all stages of disease are allowed; also eligible are patients who have started or completed one or more cycles of treatment as part of a planned first line regimen, or those who have received local radiation or surgery or corticosteroids for disease control
- •Planned treatment with standard first line therapy for non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL)
- •Karnofsky performance score >= 70%
- •Subjects must agree to use effective means to prevent conception from enrollment through completion of the study
- •Female subjects: if of child bearing potential, must have negative serum or urine pregnancy test within 7 days of enrollment
- •Subjects must be on a prophylactic regimen for Pneumocystis jiroveci pneumonia, or agree to begin such treatment, if CD4+ cell counts are observed to be =< 200/ul in peripheral blood
- •Able to understand, and the willingness to give, informed consent for the study
排除标准
- •Central nervous system (CNS) lymphoma: CNS involvement by lymphoma, including parenchymal brain or spinal cord lymphoma or known presence of leptomeningeal disease prior to registration
- •Patients with renal, hepatic, pulmonary, or cardiac disease that exclude delivery of standard chemotherapy
- •Active (uncontrolled) infection requiring systemic antibiotic therapy with antibacterial, antifungal, or antiviral agents (excluding HIV)
- •Hepatitis B surface antigen positive
- •Hepatitis C virus (HCV) antibody positive and detectable HCV quantitative ribonucleic acid (RNA), with clinical evidence of cirrhosis as determined by the principal investigator
- •Requiring active treatment for Toxoplasma gondii infection
- •Malignancy other than lymphoma, unless (1) in complete remission and more than 5 years from last treatment, or (2) cervical/anal squamous cell carcinoma in situ or (3) superficial basal cell and squamous cell cancers of the skin
- •History of HIV-associated encephalopathy; dementia of any kind; seizures in the past 12 months
- •Any perceived inability to directly provide informed consent (note: consent may not be obtained by means of a legal guardian)
- •Any concurrent or past medical condition that, in the opinion of the investigator, would exclude the subject from participation
- •Patients who have received a vaccine for HIV-1 or any prior gene modified cell product, at any time
- •A medical history of noncompliance with HAART or medical therapy
- •Pregnant women or nursing mothers
- •Use of zidovudine as part of the HAART regimen (a drug substitution for zidovudine at the time of study entry is allowed)
- •Known hypersensitivity to any of the products used in the trial - G-CSF (Neupogen, filgrastim), plerixafor (Mozobil), or any components of the chemotherapeutic agents or O6BG/BCNU in vivo selection regimens
研究组 & 干预措施
Treatment (gene modified HPSC)
See Detailed Description.
干预措施: C46/CCR5/P140K Lentiviral Vector-transduced Autologous HSPCs (Biological)
Treatment (gene modified HPSC)
See Detailed Description.
干预措施: Carmustine (Drug)
Treatment (gene modified HPSC)
See Detailed Description.
干预措施: Filgrastim (Biological)
Treatment (gene modified HPSC)
See Detailed Description.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (gene modified HPSC)
See Detailed Description.
干预措施: O6-Benzylguanine (Drug)
Treatment (gene modified HPSC)
See Detailed Description.
干预措施: Plerixafor (Drug)
结局指标
主要结局
Feasibility of collection: defined as collection of >= 4.0 x 10^6 CD34+ cells/kg for genetic modification
时间窗: Up to 28 days after completion of last course of first line treatment for lymphoma
Feasibility of infusion of gene modified cells: defined as engraftment of >= 1% gene modified cells
时间窗: Up to 28 days after infusion of gene-modified cells to 15 years post-transfusion
Engraftment of \>= 1% gene modified cells.
Feasibility of O6-benzylguanine/carmustine in vivo selection: defined as selection of gene modified cells to a level >= 10% of peripheral blood cells
时间窗: Up to 180 days after infusion of the gene modified hematopoietic stem progenitor cells
Feasibility of structured treatment interruption: defined as the ability to achieve >= 10% gene modified cell engraftment level and maintain CD4 counts and plasma viremia at levels required for structured treatment interruption eligibility
时间窗: Up to 18 months following infusion of CD34+ gene modified hematopoietic stem progenitor cells
Presence of confirmed replication competent lentivirus
时间窗: Up to 15 years
Any development of confirmed replication competent lentivirus in any patient receiving gene modified cells during the study will be recorded.
Presence of insertional mutagenesis
时间窗: Up to 15 years
Confirmed insertional mutagenesis in any patient who received gene modified cells during the study
Safety of infusion of gene modified cells: defined as Common Terminology Criteria for Adverse Events version 4 toxicity >= grade 3 related to the infusion of gene modified cells
时间窗: Up to 30 days after infusion of CD34+ modified hematopoietic stem progenitor cells
Safety of O6-benzylguanine/carmustine in vivo selection, defined as < 25% of patients developing Common Terminology Criteria for Adverse Events version 4 toxicity >= grade 3 associated with O6-benzylguanine/carmustine administration
时间窗: Up to 15 years
次要结局
未报告次要终点