Phase I Study To Evaluate Cellular Adoptive Immunotherapy Using Autologous IL-21 Modulated CD8+ Antigen-Specific T Cells For Patients With Metastatic Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Safety and toxicity as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0
研究概览
简要总结
RATIONALE: Aldesleukin may stimulate lymphocytes to kill melanoma cells. Treating lymphocytes with interleukin-21 in the laboratory may help the lymphocytes kill more tumor cells when they are put back in the body. Giving therapeutic autologous lymphocytes together with cyclophosphamide and aldesleukin may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of giving therapeutic autologous lymphocytes together with cyclophosphamide and aldesleukin in treating patients with metastatic melanoma
详细描述
PRIMARY OBJECTIVES:
I. Assess the safety and toxicity of adoptively transferred interleukin (IL)-21 modulated cytotoxic T-lymphocyte (CTL) targeting a melanoma associated antigen in patients following cyclophosphamide conditioning.
II. Evaluate the functional and numeric in vivo persistence of adoptively transferred IL-21 modulated CTL and factors contributing to immunopotentiation in patients receiving IL-21 modulated CTL following cyclophosphamide conditioning.
SECONDARY OBJECTIVES:
I. Evaluate the antitumor effect of adoptively transferred IL-21 modulated CD8+ antigen-specific CTL following cyclophosphamide conditioning and post-infusion IL-2.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •FOR LEUKAPHERESIS:
- •Pulse > 45 or < 120
- •Weight >= 45 kg
- •Temperature =< 38 Celsius (C) (=< 100.4 Fahrenheit [F])
- •White blood cells (WBC) >= 3000
- •Hematocrit (HCT) >= 30%
- •Platelets >= 100,000
- •FOR T CELL INFUSION:
- •Histopathological documentation of melanoma concurrent with the diagnosis of metastatic disease
- •Tumor expression of MART-1 (2+ staining or > 25%) by immunohistochemistry (IHC)
- •Able to tolerate high-dose cyclophosphamide
- •Expression of human leukocyte antigen (HLA)-A2
- •Zubrod performance status of 0-1
- •Bi-dimensionally measurable disease by palpation on clinical exam, or radiographic imaging (X-ray, computed tomography [CT] scan)
- •Normal cardiac stress test within 182 days prior to enrollment is required of all patients over 50 years old or those with an abnormal electrocardiogram (ECG), any history of cardiac disease, a family history of cardiac disease or hypertension
排除标准
- •Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within two weeks prior to entry
- •Serum creatinine > 1.6 mg/dL or creatinine clearance (CrCl) < 75 ml/min (calculated: Cockcroft and Gault equation: CrCl = (140 - age) x ideal body weight (IBW)/(serum creatinine [Scr] x 72) (x 0.85 for females)
- •Serum glutamic oxaloacetic transaminase (SGOT) > 150 IU or > 3 x upper limit of normal
- •Direct bilirubin > 1.0 mg/dL
- •Prothrombin time > 1.5 x control (in the absence of systemic anticoagulation)
- •Clinically significant pulmonary dysfunction, as determined by medical history and physical exam; patients so identified will undergo pulmonary functions testing at the discretion of their primary physician
- •Significant cardiovascular abnormalities as defined by any one of the following:
- •Congestive heart failure,
- •Clinically significant hypotension,
- •Symptoms of coronary artery disease,
- •Presence of cardiac arrhythmias on electrocardiogram (EKG) requiring drug therapy
- •Symptomatic central nervous system metastases greater than 1 cm at time of therapy; patients with 1-2 asymptomatic, less than 1cm brain/central nervous system (CNS) metastases without significant edema may be considered for treatment; if sub-centimeter CNS lesions are noted at study entry, then a repeat imaging will be performed if more than 3 weeks have elapsed from the last scan; patients will not be treated if CNS lesions are > 1 cm or if patient is symptomatic from brain metastasis
- •Patients with active infections or oral temperature > 38.2 C within 72 hours of study entry or systemic infection requiring chronic maintenance or suppressive therapy
- •Chemotherapeutic agents (standard or experimental), radiation therapy, or other immunosuppressive therapies less than 3 weeks prior to T cell therapy; (patients with bulky disease may undergo cytoreductive chemotherapy but treatment will be discontinued at least 3 weeks prior to T cell therapy)
- •Clinically significant autoimmune disorders or conditions of immunosuppression; patients with acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV)-1 associated complex or known to HIV antibody seropositive or known to be recently polymerase chain reaction positive (PCR+) for hepatitis are not eligible for this study; virology testing will be done within 6 months of T cell infusion; the severely depressed immune system found in these infected patients and the possibility of premature death would compromise study objectives
- •Patients who, in the opinion of their physician, are not clinically suited for high-dose cytoxan
研究组 & 干预措施
Treatment (immunostimulant, autologous lymphocytes, and chemo)
Patients receive cyclophosphamide IV on days -3 and -2 followed by an infusion of IL-21 modulated, MART-1 specific CD8+ cytotoxic T lymphocytes over 30-60 minutes on day 0. Beginning within 24 hours of T cell infusion, patients receive low-dose aldesleukin SC BID for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: therapeutic autologous lymphocytes (Biological)
Treatment (immunostimulant, autologous lymphocytes, and chemo)
Patients receive cyclophosphamide IV on days -3 and -2 followed by an infusion of IL-21 modulated, MART-1 specific CD8+ cytotoxic T lymphocytes over 30-60 minutes on day 0. Beginning within 24 hours of T cell infusion, patients receive low-dose aldesleukin SC BID for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: aldesleukin (Biological)
Treatment (immunostimulant, autologous lymphocytes, and chemo)
Patients receive cyclophosphamide IV on days -3 and -2 followed by an infusion of IL-21 modulated, MART-1 specific CD8+ cytotoxic T lymphocytes over 30-60 minutes on day 0. Beginning within 24 hours of T cell infusion, patients receive low-dose aldesleukin SC BID for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: cyclophosphamide (Drug)
Treatment (immunostimulant, autologous lymphocytes, and chemo)
Patients receive cyclophosphamide IV on days -3 and -2 followed by an infusion of IL-21 modulated, MART-1 specific CD8+ cytotoxic T lymphocytes over 30-60 minutes on day 0. Beginning within 24 hours of T cell infusion, patients receive low-dose aldesleukin SC BID for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: biopsy (Procedure)
结局指标
主要结局
Safety and toxicity as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0
时间窗: 10 weeks post infusion
Functional and numeric in vivo persistence of adoptively transferred IL-21 modulated CTL and factors contributing to immunopotentiation in patients receiving IL-21 modulated CTL following cyclophosphamide conditioning
时间窗: 10 weeks post infusion
Descriptive statistics (average, median standard deviation and student's t test) will be used to determine if an increase in the duration of in vivo persistence is observed using IL-21 modulated T cells when retrospectively compared with T cells generated under standard culture conditions (no IL-21 exposure in vitro).
次要结局
- In vivo persistence and anti-tumor effect of the infused IL-21 modulated CTL(10 weeks post infusion)