Study to Infuse Haploidentical Natural Killer Cells in Patients With Relapsed or Refractory Neuroblastoma
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- Participant Disease Response
研究概览
简要总结
Primary:
Evaluate safety, feasibility, persistence, and anti-tumor effect of infused haploidentical donor-derived natural killer (NK) cells and low-dose interleukin-2 (IL-2).
Secondary:
- Quantification of cytokine levels;
- Assessment of NK cell immunophenotype and function.
详细描述
Experimental Therapy:
NK cells are part of the immune system (the cells in the body that naturally fight disease and infection). NK cells can sometimes destroy tumor cells, and they may be better at destroying tumor cells when the NK cells are "mismatched" for certain proteins called human leukocyte antigens (HLA). This can be determined by looking at the donor's and the recipient's HLA types and by checking for other specialized proteins on the donor's NK cells (called killer immunoglobulin receptors [KIR]).
The NK cells will be collected from the donor's blood and then processed using an experimental device called a CliniMACS device. This device is designed to separate out the NK cells from the rest of the donor's collected white blood cells, using a special magnet. Before being infused into the recipient (you, if you choose to take part), the collected NK cells will be treated with a study drug called interleukin-2 (IL-2) in order to try to activate the NK cells' killing ability. You will also receive IL-2 injections to try to help the NK cells survive after infusion and possibly increase in number.
Screening Tests:
Within 28 days before you can start treatment on this study, you will have "screening tests" to help the study doctor decide if you are eligible to take part in this study. The following tests will be performed:
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
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion Criteria: (Must be met within 28 days prior to initiating lymphodepleting conditioning regimen) The first two patients enrolled in this protocol, if they have undergone a previous autologous transplant, will need to be at least 6 months post-transplant and/or have available prior cryopreserved autologous peripheral blood stem cells. This criterion safeguards against the possibility that the lymphodepletion regimen may lead to prolonged myelosuppression in this patient population.
- •Evidence of relapse or progression of neuroblastoma after autologous peripheral blood stem-cell transplantation or similar aggressive therapy; high risk neuroblastoma that is refractory to standard induction therapy.
- •Measurable disease, with at least one of the following: One or more measurable radiographic abnormalities (X-ray, CT, MRI, PET); MIBG (metaiodobenzylguanidine) scan with uptake at a minimum of 1 site; Bone marrow with tumor cells seen on routine morphology (not by neuron specific enolase (NSE) staining or by immunocytology only). If the only bony or soft tissue lesion available for evaluation has been previously irradiated, the lesion must either a) have viable neuroblastoma on biopsy at least 4 weeks after radiation therapy or b) have measurable growth in the lesion after radiation.
- •Donor must be related to the recipient.
- •Off all systemic chemotherapeutic agents or retinoids for at least 21 days prior to NK infusion.
- •Platelets >/= 50,000 * 10^ 9/L and hemoglobin (Hgb) >/= 9 g/dL, unsupported by transfusions in last seven days.
- •absolute neutrophil count (ANC) >/= 1,000 * 10^ 9/L, unsupported by cytokines in last seven days.
- •Off prednisone or other immunosuppressive medications for at least 3 days prior to both the lymphodepleting regimen and the NK infusion (This excludes chronic low dose steroids for adrenal replacement which may be continued).
- •Karnofsky score or Lansky score >/=
- •Adequate renal function defined as: Serum creatinine (Cr), for adults less than or equal to 2 mg/dL, for children less than or equal to 2 mg/dL or less than or equal to 2 times upper limit of normal (ULN) for age (whichever is less). If these criteria are not met, then recipient must have a Cr clearance greater than 60 mL/min/1.73m^
- •Adequate liver function defined as: Total bilirubin </=2 mg/dL and serum glutamate pyruvate transaminase (SGPT/Alanine aminotransferase, ALT) </= 2.5 * ULN for age (unless Gilbert's disease or abnormal liver function due to primary disease).
- •Pulmonary symptoms controlled by medication and pulse oximetry greater than or equal to 92% room air.
- •Females of childbearing potential (non childbearing is defined as premenarchal, greater than one year post-menopausal or surgically sterilized) must have a negative serum pregnancy test obtained within 2 weeks prior to registration and may not be breast feeding during the study. All males and females of childbearing potential are required to use a form of contraception considered effective and medically acceptable by the Investigator during the time of the study.
- •Donor must meet standard medical eligibility criteria for allogeneic stem cell donation and be able and willing to undergo apheresis.
- •Donor must have infectious disease marker testing [Hepatitis B, Hepatitis C, HIV, cytomegalovirus (CMV), Syphilis (RPR), Chagas, human T-cell lymphoma virus (HTLV), and West Nile Virus] and complete blood count (CBC), differential and platelet studies that meet standard medical eligibility criteria for allogeneic blood stem cell donation within 7 days of apheresis.
- •Donor, if a female of childbearing potential (non-childbearing is defined as premenarchal, greater than one year post-menopause or surgically sterilized), must have a negative serum pregnancy test obtained within 14 days of apheresis and may not be breast feeding.
排除标准
- •Exclusion Criteria: These criteria apply to both the start of the lymphodepleting regimen and to the NK infusion
- •Evidence of HIV (human immunodeficiency virus) disease or positive serology for HIV.
- •Currently requiring supplemental oxygen or on a ventilator.
- •Currently undergoing dialysis.
- •New detected cardiac arrhythmia not controlled with medical management within prior 72 hour period.
- •Hypotension requiring pressor support within prior 72 hour period.
- •Uncontrolled infection, daily fever greater than or equal to 39 degrees Celsius or new positive culture for bacteria, fungus, or virus within the 72 hours prior to NK-cell infusion.
- •Ascites requiring paracentesis within prior 72 hour period.
- •Seizure activity, clinically detectable encephalopathy or new focal neurologic deficits within prior 72 hour period.
- •Donor may not have an uncontrolled infection within 7 days of apheresis.
研究组 & 干预措施
Fludarabine + Cyclophosphamide + NK Cell Infusion
Fludarabine 25 mg/m^2 intravenous (IV) Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2. Cyclophosphamide 60 mg/kg IV Daily Over 2 Hours On Days -5 and -4. Natural Killer Cell Infusion on Day 0. Mesna 12 mg/kg By Vein, Over about 15 minutes, 5 Times Per Day on Days -5 and -4. Interleukin-2 subcutaneously three times weekly for 9 total doses following NK Cell Infusion.
干预措施: Fludarabine (Drug)
Fludarabine + Cyclophosphamide + NK Cell Infusion
Fludarabine 25 mg/m^2 intravenous (IV) Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2. Cyclophosphamide 60 mg/kg IV Daily Over 2 Hours On Days -5 and -4. Natural Killer Cell Infusion on Day 0. Mesna 12 mg/kg By Vein, Over about 15 minutes, 5 Times Per Day on Days -5 and -4. Interleukin-2 subcutaneously three times weekly for 9 total doses following NK Cell Infusion.
干预措施: Cyclophosphamide (Drug)
Fludarabine + Cyclophosphamide + NK Cell Infusion
Fludarabine 25 mg/m^2 intravenous (IV) Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2. Cyclophosphamide 60 mg/kg IV Daily Over 2 Hours On Days -5 and -4. Natural Killer Cell Infusion on Day 0. Mesna 12 mg/kg By Vein, Over about 15 minutes, 5 Times Per Day on Days -5 and -4. Interleukin-2 subcutaneously three times weekly for 9 total doses following NK Cell Infusion.
干预措施: Natural Killer Cell Infusion (Biological)
Fludarabine + Cyclophosphamide + NK Cell Infusion
Fludarabine 25 mg/m^2 intravenous (IV) Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2. Cyclophosphamide 60 mg/kg IV Daily Over 2 Hours On Days -5 and -4. Natural Killer Cell Infusion on Day 0. Mesna 12 mg/kg By Vein, Over about 15 minutes, 5 Times Per Day on Days -5 and -4. Interleukin-2 subcutaneously three times weekly for 9 total doses following NK Cell Infusion.
干预措施: Mesna (Drug)
Fludarabine + Cyclophosphamide + NK Cell Infusion
Fludarabine 25 mg/m^2 intravenous (IV) Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2. Cyclophosphamide 60 mg/kg IV Daily Over 2 Hours On Days -5 and -4. Natural Killer Cell Infusion on Day 0. Mesna 12 mg/kg By Vein, Over about 15 minutes, 5 Times Per Day on Days -5 and -4. Interleukin-2 subcutaneously three times weekly for 9 total doses following NK Cell Infusion.
干预措施: Interleukin-2 (Drug)
结局指标
主要结局
Participant Disease Response
时间窗: 1 Year for overall patient response, or until disease progression
Neuroblastoma International Response Criteria: Complete Response (CR): No evidence of disease (primary and metastasis) clinically \& radiographic studies, (homovanillic acid (HVA)/vanillylmandelic acid (VMA) normal). Very Good Partial Response (VGPR): \>90% reduction in primary tumor, resolution all metastatic tumor except bone. No new bone lesions and improvement on scan of all pre-existing lesions; HVA/VMA decreased \>90%. Partial Response (PR): 50-90% reduction primary and all measurable metastatic lesions, 0-1 bone marrow samples with tumor; scans of bone lesions same as VGPR. HVA/VMA decreased 50-90%. Mixed Response (MR): \> 50% reduction any measurable disease (primary or metastases); no new lesions; \<25% increase in any existing lesion (exclude bone marrow evaluation). No Response (NR): No new lesions; \< 25% increase in existing lesion. Progressive Disease (PD): Any new lesions. Increase \<25% in measurable lesion, previous negative bone marrow positive for tumor.
Number of Participants Infused Haploidentical Donor-derived Natural Killer (NK) Cells and Low-dose Interleukin-2 (IL-2)
时间窗: 21 days, up to 1 year
Feasibility of an infused allogeneic donor NK cell product and IL-2 following a cyclophosphamide and fludarabine preparative regimen to treat relapsed neuroblastoma after autologous peripheral blood stem cell (PBSC) transplant where feasibility is defined as being able to infuse NK cells on day 0.
次要结局
未报告次要终点