AUTOLOGOUS TRANSPLANTATION AND STEM CELL BASED-GENE THERAPY FOR THE TREATMENT OF HIV-ASSOCIATED LYMPHOMA
试验速览
- 阶段
- 不适用
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Safety of O6BG/BCNU in vivo selection, defined as less than 25% of patients developing grade 3 or greater non-hematopoietic toxicity or grade 4 CTCv.4 hematopoietic toxicity
研究概览
简要总结
This clinical trial studies genetically modified peripheral blood stem cell transplant in treating patients with HIV-associated non-Hodgkin or Hodgkin lymphoma. Giving chemotherapy before a peripheral stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy or radiation therapy is then given to prepare the bone marrow for the stem cell transplant. Laboratory-treated stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and radiation therapy
详细描述
PRIMARY OBJECTIVES:
I. To determine the safety and feasibility of infusing gene-modified, human immunodeficiency virus (HIV)-protected hematopoietic stem cells (HSC) after high-dose chemotherapy for treatment of acquired immunodeficiency syndrome (AIDS)-related lymphoma.
II. To determine the dose of carmustine (BCNU) in combination with O^6-benzylguanine (O6BG) that results in selection in vivo of gene-modified HIV-resistant cells.
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 antiviral treatment 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 seropositive
- •Antiretroviral treatment for at least one month, defined as a multi-drug regimen (excluding azacitidine [AZT])
- •HIV plasma viral load has decreased by 1.5 logs or viral load < 5000 copies/ml
- •Non-Hodgkin or Hodgkin lymphoma without active central nervous system (CNS) involvement associated with poor prognosis with medical therapy alone or for which autologous peripheral blood stem cell (PBSC) transplant is indicated:
- •Hodgkin's lymphoma beyond first remission; first partial remission; induction failure with subsequent response to salvage therapy
- •Non-Hodgkin's Lymphoma beyond first remission: first partial remission; induction failure with subsequent response to salvage therapy
- •Chemotherapy responsive disease
- •Karnofsky performance score >= 70%
- •Subjects must agree to use effective contraception 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 treatment
- •Subjects must be on a prophylactic regimen for Pneumocystis carinii pneumonia, or agree to begin such treatment, if the cluster of differentiation (CD)4 counts are =< 200
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •Serum creatinine > 2 times upper limit of normal
- •Serum bilirubin greater than 3 times the upper limits of normal, unless determined to be a result of the primary hematologic malignancy or attributed to Gilbert's syndrome
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limits of normal, unless determined to be a result of the primary hematologic malignancy or attributed to Gilbert's syndrome
- •Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) or diffusion capacity of the lung of carbon monoxide (DLCO) parameters < 60% predicted (corrected for hemoglobin)
- •Left ventricular ejection fraction (LVEF) < 50% or coronary artery disease requiring treatment
- •Active infection requiring systemic antibiotic therapy with antibacterial, antifungal, or antiviral agents (excluding HIV)
- •Patients who are hepatitis C virus (HCV) antibody positive or hepatitis B virus (HBV) surface antigen positive must be free of clinical evidence of cirrhosis that would otherwise make them ineligible for HCT, as determined by the Principal Investigator (P.I.) in consultation with the Gastrointestinal Service; patients with HBV and ongoing evidence of viral replication may require therapy prior to receiving high-dose chemotherapy
- •Positive serology for Toxoplasma gondii AND requiring treatment or with evidence of active 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)
- •A medical history of noncompliance with highly active anti-retroviral therapy (HAART) or medical therapy
研究组 & 干预措施
Treatment (gene modified peripheral blood cell transplant)
CONDITIONING: Patients receive carmustine IV over 3 hours on day -7, cytarabine IV over 2 hours BID and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2.
TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0.
Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection.
干预措施: carmustine (Drug)
Treatment (gene modified peripheral blood cell transplant)
CONDITIONING: Patients receive carmustine IV over 3 hours on day -7, cytarabine IV over 2 hours BID and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2.
TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0.
Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection.
干预措施: cytarabine (Drug)
Treatment (gene modified peripheral blood cell transplant)
CONDITIONING: Patients receive carmustine IV over 3 hours on day -7, cytarabine IV over 2 hours BID and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2.
TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0.
Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection.
干预措施: melphalan (Drug)
Treatment (gene modified peripheral blood cell transplant)
CONDITIONING: Patients receive carmustine IV over 3 hours on day -7, cytarabine IV over 2 hours BID and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2.
TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0.
Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection.
干预措施: etoposide (Drug)
Treatment (gene modified peripheral blood cell transplant)
CONDITIONING: Patients receive carmustine IV over 3 hours on day -7, cytarabine IV over 2 hours BID and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2.
TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0.
Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection.
干预措施: O6-benzylguanine (Drug)
Treatment (gene modified peripheral blood cell transplant)
CONDITIONING: Patients receive carmustine IV over 3 hours on day -7, cytarabine IV over 2 hours BID and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2.
TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0.
Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection.
干预措施: autologous hematopoietic stem cell transplantation (Procedure)
Treatment (gene modified peripheral blood cell transplant)
CONDITIONING: Patients receive carmustine IV over 3 hours on day -7, cytarabine IV over 2 hours BID and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2.
TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0.
Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection.
干预措施: peripheral blood stem cell transplantation (Procedure)
Treatment (gene modified peripheral blood cell transplant)
CONDITIONING: Patients receive carmustine IV over 3 hours on day -7, cytarabine IV over 2 hours BID and etoposide IV over 2 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2.
TRANSPLANTATION: Patients receive an autologous PBSC infusion and/or infusion of autologous transduced hematopoietic cells on day 0.
Beginning 28-120 days later, patients eligible for in vivo selection after detection of gene-marked cells receive O6-benzylguanine IV over 1 hour and carmustine IV over 3 hours on days 14, 28, and then monthly until completion of therapy. Patients achieving > 10% gene marking and CD4 count of >= 500 cells/uL receive up to 2 courses of structured treatment interruption without undergoing in vivo selection.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Safety of O6BG/BCNU in vivo selection, defined as less than 25% of patients developing grade 3 or greater non-hematopoietic toxicity or grade 4 CTCv.4 hematopoietic toxicity
时间窗: Up to day 180
Safety of infusion of gene-modified cells, measured by grade 3 or greater toxicities related to infusion of gene-modified cells using the Common Toxicity Criteria version 4.0(CTCv.4)
时间窗: Up to day 180
Efficacy of O6BG/BCNU in vivo selection, defined as selection of gene-modified cells to a level at least 10% of peripheral blood cells
时间窗: Up to 3 months
Efficacy of gene transduction, defined as collection of more than 4.5 x 10^6 CD34+ cells/kg cells for genetic modification and evidence of gene-marked cells before HSC infusion
时间窗: Up to 3 months
Safety of structured treatment interruption defined as no decline in CD4 count by more than 25%, no HIV RNA more than 10,000 copies/mL; and no elevation of immune activation markers
时间窗: During the 12 weeks without HAART
Efficacy of infusion of gene-modified cells, defined as engraftment of at least1% gene-modified cells
时间窗: Up to 3 months
次要结局
未报告次要终点