Phase I/II Trial of Cord Blood-Derived NK Cells Genetically Engineered With NY-ESO-1 TCR/IL-15 Cell Receptor for Relapsed/Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 44
- 试验地点
- 2
- 主要终点
- Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
研究概览
简要总结
To find the recommended dose of NY-ESO-1 TCR/IL-15 NK cells that can be given to patients with relapsed or refractory MM.
To learn if the dose of NY-ESO-1 TCR/IL-15 NK cells found in Part A can help to control the disease.
详细描述
Primary Objectives:
- Part A: To assess dose-limiting toxicity (DLT) and determine the safety and optimal cell dose of NY-ESO-1 TCR/IL-15 NK cells in patients with relapsed/refractory multiple myeloma.
- Part B: To assess the day +90 overall response rate in patients treated at the optimal cell dose.
Secondary Objectives:
- Assess day +180 progression-free survival (PFS).
- Quantify the persistence of infused allogeneic donor TCR-transduced CB-derived NK cells in the recipient.
- To conduct comprehensive immune reconstitution studies.
- To obtain preliminary data on quality of life and patient experience.
- Assess duration of response (DOR)
Secondary end points
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Patients with multiple myeloma with an expression of NY-ESO-1 by immunohistochemistry in the pre-screening or screening tumor sample or PCR NY-ESO-1 testing by Pathology. CD138 by immunostains will be performed to identify plasma cells before testing for NY-ESO-1
- •Patients are HLA-A*02:01, HLA-A*2:05, or HLA-A*2:06 positive on human leukocyte antigen (HLA) typing at any time.
- •3. Patients with relapsed or refractory multiple myeloma (MM) (patients with solitary plasmacytoma are not eligible) who meet the following criteria:
- •> or = 2 prior lines of therapy (including exposure to at least one proteasome inhibitor, immunomodulatory imide drug [ImiD], and anti-cd38 antibody and refractory to the last line of therapy)
- •Have measurable disease (serum monoclonal [M] protein level ≥ 0.5 g/dL, and/or urine M protein level ≥ 200 mg/24hrs, and/or involved serum free light chain [FLC] level ≥10 mg/dL provided the serum-free light-chain ratio is abnormal) ** Refractory is defined as a documented progressive disease during or within 60 days (measured from the last dose of any drug within the regimen) of completing treatment with the last anti-myeloma regimen before study entry
- •No anti-myeloma therapy within 7 days of lymphodepleting therapy. Note: Steroids are allowed at any time up until lymphodepletion. Localized radiation for palliation is allowed at any time up until NK cell infusion
- •Prior autologous/allogeneic transplants are allowed.
- •Prior cell therapy is allowed against targets other than NY-ESO-
- •Patients must have recovered from systemic toxicity of prior anti-myeloma therapy at the start of lymphodepletion
- •Eastern Cooperative Oncology Group (ECOG) performance status <= 2
- •Estimated glomerular filtration rate (eGFR using the Chronic Kidney Disease Epidemiology Collaboration [CKI-EPI] equation) >= 30 ml/min/1.73 m^2
- •Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) or =< 5 x ULN if documented liver metastases
- •Total bilirubin =< 1.5 mg/dL, except in subjects with Gilbert's syndrome in whom total bilirubin must be =< 3.0 mg/dL
- •No history of liver cirrhosis
- •Cardiac ejection fraction >= 50%
- •No clinically significant pericardial effusion as determined by an ECHO or MUGA
- •No uncontrolled arrhythmias or symptomatic cardiac disease
- •No clinically significant pleural effusion (per principal investigator [PI] discretion)
- •Baseline oxygen saturation > 92% on room air
- •Able to provide written informed consent
- •18-80 years of age
- •Weight ≥ 40 kg
- •Absolute neutrophil count (ANC) ≥ 1000 /
- •Note: Growth factor support is allowed prior to lymphodepletion chemotherapy (LD chemo). Transfusion support is allowed at any time. If cytopenias are related to multiple myeloma, the patient may proceed without meeting above hematologic parameters only if bone marrow plasma cells are >= 50%
- •Hemoglobin ≥ 8 g/dL
- •Note: Growth factor support is allowed prior to LD chemo. Transfusion support is allowed at any time. If cytopenias are related to multiple myeloma, the patient may proceed without meeting above hematologic parameters only if bone marrow plasma cells are >= 50%
- •Platelet count >= 25,000 /uL
- •Note: Growth factor support is allowed prior to LD chemo. Transfusion support is allowed at any time. If cytopenias are related to multiple myeloma, the patient may proceed without meeting above hematologic parameters only if bone marrow plasma cells are >= 50%
- •All participants who are able to have children must practice effective birth control while on study and up to 3 months post completion of study therapy. Acceptable forms of birth control for female patients include: hormonal birth control, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence, for the length of the study. If the participant is a female and becomes pregnant or suspects pregnancy, she must immediately notify her doctor. If the participant becomes pregnant during this study, she will be taken off this study. The study team will ask for information about the pregnancy
- •Men who are able to have children must use effective birth control while on the study. If the male participant fathers a child or suspects that he has fathered a child while on the study, he must immediately notify his doctor
- •Signed consent to long-term follow-up protocol PA17-0483 to fulfill the institutional responsibilities to various regulatory agencies
- •Patients with relapsed or refractory plasma cell leukemia who have received at least two previous regimens
- •CRITERIA FOR LYMPHODEPLETION:
- •Patient should continue to meet eligibility criteria above with the following exceptions:
- •* Platelet count >/= 25,000 /μL
- •** Note: Growth factor support is allowed prior to LD chemo. Transfusion support is allowed at any time. If cytopenias are related to multiple myeloma, the patient may proceed without meeting above hematologic parameters only if bone marrow plasma cells are >= 50%
- •CRITERIA FOR CELL INFUSION:
- •Patients who meet one of the following criteria on the day of infusion will have their administration delayed for 24 hours. If these problems persist beyond 24 hours, patients will not receive their cell infusion.
- •Cardiac arrhythmias not controlled with medical management
- •Hypotension requiring vasopressor support
- •Suspected or active uncontrolled infection
排除标准
- •Active or uncontrolled infection at the start of lymphodepletion and/or cell infusion
- •Patients with concurrent autoimmune diseases with neurologic involvement, such as multiple sclerosis
- •Participants who have received any live vaccines within 30 days prior to study entry
- •Any active infection requiring systematic antibiotics
- •Any evidence of another malignancy within the last 2 years prior to screening that has not been treated with curative intent (except in situ non-melanoma skin cell cancers and/or carcinoma in-situ of the cervix or other conditions that are deemed low-risk after discussion with the medical monitor)
- •Any major surgery within 28 days of lymphodepletion, minor surgery within 14 days of lymphodepletion, or any planned medical or surgical procedure that in the opinion of the investigator, might jeopardize the patient's safety
研究组 & 干预措施
Part A2: Cell therapy with NY-ESO-1 TCR/IL-15 NK - OUTPATIENT
干预措施: Fludarabine phosphate (Drug)
Part A: Cell therapy with NY-ESO-1 TCR/IL-15 NK - INPATIENT
干预措施: Fludarabine phosphate (Drug)
Part A: Cell therapy with NY-ESO-1 TCR/IL-15 NK - INPATIENT
干预措施: Cyclophosphamide (Drug)
Part A: Cell therapy with NY-ESO-1 TCR/IL-15 NK - INPATIENT
干预措施: NY-ESO-1 TCR/IL-15 NK (Drug)
Part A2: Cell therapy with NY-ESO-1 TCR/IL-15 NK - OUTPATIENT
干预措施: Cyclophosphamide (Drug)
Part A2: Cell therapy with NY-ESO-1 TCR/IL-15 NK - OUTPATIENT
干预措施: NY-ESO-1 TCR/IL-15 NK (Drug)
Part B: Cell therapy with NY-ESO-1 TCR/IL-15 NK - INPATIENT
干预措施: Fludarabine phosphate (Drug)
Part B: Cell therapy with NY-ESO-1 TCR/IL-15 NK - INPATIENT
干预措施: Cyclophosphamide (Drug)
Part B: Cell therapy with NY-ESO-1 TCR/IL-15 NK - INPATIENT
干预措施: NY-ESO-1 TCR/IL-15 NK (Drug)
Part B2: Cell therapy with NY-ESO-1 TCR/IL-15 NK - OUTPATIENT
干预措施: Fludarabine phosphate (Drug)
Part B2: Cell therapy with NY-ESO-1 TCR/IL-15 NK - OUTPATIENT
干预措施: Cyclophosphamide (Drug)
Part B2: Cell therapy with NY-ESO-1 TCR/IL-15 NK - OUTPATIENT
干预措施: NY-ESO-1 TCR/IL-15 NK (Drug)
Treatment (lymphodepletion, NY-ESO-1 TCR/IL-15 NK cells)
Patients receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3, followed by NY-ESO-1 TCR/IL-15 NK cells IV over 1-40 minutes on day 0. Patients who fail to achieve CR after receiving NY-ESO-1 TCR/IL-15 NK cells may receive up to 3 additional doses of NY-ESO-1 TCR/IL-15 NK cells and preceding lymphodepleting chemotherapy at 12 to 16 week intervals from day +0 of the previous cycle until the patient achieves CR or has completed a total of 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo chest x-ray and ECHO or MUGA at screening, and undergo collection of blood samples, PET/CT scans and bone marrow aspiration/biopsy throughout the trial.
干预措施: Fludarabine phosphate (Drug)
Treatment (lymphodepletion, NY-ESO-1 TCR/IL-15 NK cells)
Patients receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3, followed by NY-ESO-1 TCR/IL-15 NK cells IV over 1-40 minutes on day 0. Patients who fail to achieve CR after receiving NY-ESO-1 TCR/IL-15 NK cells may receive up to 3 additional doses of NY-ESO-1 TCR/IL-15 NK cells and preceding lymphodepleting chemotherapy at 12 to 16 week intervals from day +0 of the previous cycle until the patient achieves CR or has completed a total of 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo chest x-ray and ECHO or MUGA at screening, and undergo collection of blood samples, PET/CT scans and bone marrow aspiration/biopsy throughout the trial.
干预措施: Cyclophosphamide (Drug)
Treatment (lymphodepletion, NY-ESO-1 TCR/IL-15 NK cells)
Patients receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3, followed by NY-ESO-1 TCR/IL-15 NK cells IV over 1-40 minutes on day 0. Patients who fail to achieve CR after receiving NY-ESO-1 TCR/IL-15 NK cells may receive up to 3 additional doses of NY-ESO-1 TCR/IL-15 NK cells and preceding lymphodepleting chemotherapy at 12 to 16 week intervals from day +0 of the previous cycle until the patient achieves CR or has completed a total of 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo chest x-ray and ECHO or MUGA at screening, and undergo collection of blood samples, PET/CT scans and bone marrow aspiration/biopsy throughout the trial.
干预措施: Allogeneic Anti-NY-ESO-1-TCR-IL-15-transduced Cord Blood-derived Natural Killer Cells (Drug)
结局指标
主要结局
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
时间窗: through study completion; an average of 1 year
次要结局
未报告次要终点