Phase Ib/II Study of the Administration of T Lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) for Relapsed/Refractory CD30+ Hodgkin's Lymphoma and CD30+ Non-Hodgkin's Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 38
- 试验地点
- 1
- 主要终点
- Number of participants with adverse events as a measure of safety and tolerability of ATLCAR.CD30 cells to establish a safe dose after lymphodepletion with bendamustine in adult patients
研究概览
简要总结
The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been sufficient to cure most patients. This study is designed to combine both T cells and antibodies to create a more effective treatment called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD30 antigen (ATLCAR.CD30) administration.
In previous studies, it has been shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes an antibody called anti-CD30. This antibody sticks to lymphoma cells because of a substance on the outside of the cells called CD30. Anti-CD30 antibodies have been used to treat people with lymphoma, but have not been strong enough to cure most patients. For this study, the anti-CD30 antibody has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD30 chimeric (combination) receptor-activated T cells seem to kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown.
The purpose of this research study is to establish a safe dose of ATLCAR.CD30 cells to infuse after lymphodepleting chemotherapy and to estimate the number patients whose cancer does not progress for two years after ATLCAR.CD30 administration. This study will also look at other effects of ATLCAR.CD30 cells, including their effect on the patient's cancer.
详细描述
STUDY OBJECTIVES
Primary Objective (Phase Ib portion of Study) To establish a safe dose (ie, number cells/m2) of ATLCAR.CD30 to infuse after lymphodepletion with bendamustine in adult patients with CD30+ refractory/relapsed Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).
To establish a safe dose (ie, number cells/m2) of ATLCAR.CD30 to infuse after lymphodepletion with bendamustine and fludarabine in pediatric patients with CD30+ refractory/relapsed Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).
Primary Objective (Phase II portion of study) To estimate 2 year progression free survival (PFS) after administration of ATLCAR.CD30 in combined adult/pediatric patients with CD30+ refractory/relapsed HL and NHL
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
- 3 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Prior to Cell Procurement
- •Informed consent explained to, understood by and signed by the subject or legal guardian for pediatric subjects; subject and/or legal guradian given a copy of informed consent form for procurement
- •Ages 3 to 17 years of age for pediatric subjects (weight must be ≥10kg), and for adults ages ≥18 years of age
- •Diagnosis of recurrent HL or NHL in subjects who have failed >2 prior treatment regimens. Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for this study.
- •CD30+ disease (result can be pending at the time of cell procurement, but must be confirmed prior to treatment with ATLCAR.CD30 cells). NOTE: CD30+ disease requires documented CD30 expression by immunohistochemistry based on the institutional hematopathology standard.
- •Karnofsky or Lansky score of >60% (Karnofsky for ≥16 years old and Lansky for <16 years old)
- •Evidence of adequate organ function as defined by:
- •Hemoglobin ≥ 8.0 g/dL (transfusion independent for 2 weeks prior to enrollment)
- •Total bilirubin ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome
- •AST ≤ 3 × ULN
- •Serum creatinine ≤ 1.5 × ULN
- •For subjects <18 years old use the following table for serum creatinine requirements:
- •Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0 ≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4 ≥16 and <18 ≤1.7 ≤1.4
- •Negative serum pregnancy test in females within 72 hours prior to procurement or documentation that the subject is post-menopausal or premenarchal.
- •Women of childbearing potential (WOCBP) should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study, and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for >1 year.
- •Postmenopausal status must be confirmed with documentation of absence of menses for >1 year.
排除标准
- •Prior to Cell Procurement
- •Pregnant or lactating
- •Tumor in a location where enlargement could cause airway obstruction
- •Must not have an Active infection with human immunodeficiency virus (HIV), Hepatitis B Virus (HBV))or, Hepatitis C virus (HCV) (can be pending at the time of cell procurement; only subjects meeting the criteria as so described will be infused). Note: To meet eligibility subjects are required to have negative HIV antibody, negative for Hepatitis B surface antigen and negative for HCV antibody or viral load.
- •Inclusion Criteria Prior to Lymphodepletion
- •Informed consent explained to, understood by and signed by the subject or legal guardian for pediatric subjects; subject and/or legal guradian given a copy of informed consent form.
- •CD30+ disease (result can be pending at the time of cell procurement, but must be confirmed prior to lymphodepletion); Note: CD30+ disease requires documented CD30 expression by immunohistochemistry based on the institutional hematopathology standard.
- •Prior to administration of lymphodepletion:
- •Absolute neutrophil count (ANC) is > 1.0 × 10^9/L
- •Platelet count > 75 × 10^9/L
- •For Grade 4 neutropenia, Grade ≥3 febrile neutropenia, or Grade 4 thrombocytopenia, hold bendamustine until toxicity resolve to Grade ≤2
- •For WOCBP negative serum pregnancy test within 72 hours prior to lymphodepletion.
- •Imaging results from within 7 days (30 days in subjects with cutaneous T cell lymphoma) prior to lymphodepletion. Subjects who have received bridging chemotherapy must have imaging performed at least 3 weeks after most recent therapy (imaging does not need to be repeated if it is within 7 days prior to lymphodepletion).
- •Karnofsky or Lansky score of >60% (Karnofsky for pediatric subjects ≥16 years old and Lansky for <16 years old).
- •Available autologous transduced activated T cells that meet the Certificate of Analysis (CofA) acceptance criteria.
- •Women of childbearing potential (WOCBP) should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study, and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year.
- •Exclusion Criteria Prior to Lymphodepletion
- •Received any investigational agents or received any tumor vaccines within the previous six weeks prior to cell infusion.
- •Received anti-CD30 antibody-based therapy within the previous 4 weeks prior to cell infusion.
- •Received chemotherapy within the previous 3 weeks prior to lymphodepletion.
- •Subject has rapidly progressive disease, per treating oncologist's discretion.
- •Subject is not a good candidate for CAR T cell therapy, per treating oncologist's discretion.
- •Pregnant or lactating.
- •Tumor in a location where enlargement could cause airway obstruction.
- •Current use of systemic corticosteroids at doses equivalent of ≥10mg prednisone daily or its equivalent; those receiving <10mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed.
- •For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12 mg/m2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10mg prednisone per day. Inhaled steroids are allowed.
- •Subjects on strong inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) as these may increase plasma concentrations of bendamustine, and decrease plasma concentrations of its metabolites. See http://medicine.iupui.edu/clinpharm/ddis/ for an updated list of strong inhibitors of CYP1A
- •Details are given in the protocol.(This applies to subjects who receive bendamustine for lymphodepletion (required) up through 72 hours after the last dose of bendamustine.)
- •Active infection with HIV, HBV or HCV (can be pending at the time of cell procurement; only subjects meeting the criteria as so described will be infused. Subjects are required to have negative HIV antibody or negative for Hepatitis B surface antigen and negative HCV antibody or viral load.
- •Hepatitis B: Subjects who are positive for Hepatitis B Surface Antigen are excluded. Subjects who are Hepatitis B Surface Antigen negative but hepatitis B core Antibody positive must have their hepatitis B viral load checked. These subjects will be excluded if their viral load is positive at baseline. Subjects who are core antibody positive and viral load negative at baseline will be considered eligible if the subject has initiated an anti-HBV prophylaxis regimen prior to lymphodepletion.
- •Inclusion Criteria Prior to Infusion of ATLCAR.CD30 Cells
- •Evidence of adequate organ function as defined by:
- •Total bilirubin ≤1.5 × ULN, unless attributed to Gilbert's Syndrome
- •AST ≤3 × ULN
- •Serum creatinine ≤1.5 × ULN
- •Pulse oximetry of >90% on room air
- •For subjects <18 years old use following table for serum creatinine requirements:
- •Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0 ≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4 ≥16 and <18 ≤1.7 ≤1.4
- •Karnofsky or Lansky score of >60% (Karnofsky for ≥16 years old and Lansky for <16 years old)
- •Available autologous transduced activated T cells that meet the Certificate of Analysis (CofA) acceptance criteria.
- •Women of childbearing potential (WOCBP) should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study, and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year.
- •Exclusion Criteria Prior to Infusion of ATLCAR.CD30 Cells
- •Received any investigational agents or received any tumor vaccines within the previous six weeks prior to cell infusion.
- •Received anti-CD30 antibody-based therapy within the previous 4 weeks prior to cell infusion.
- •Tumor in a location where enlargement could cause airway obstruction.
- •Subject has rapidly progressive disease, per treating oncologist's discretion.
- •Subject is not a good candidate for CAR T cell therapy, per treating oncologist's discretion.
- •Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent; those receiving <10 mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12mg/m2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10mg prednisone per day. Inhaled steroids are allowed.
- •Active infection with HIV or HCV (can be pending at the time of cell procurement; only subjects meeting the criteria as so described will be infused). Subjects are required to be negative for HIV and negative for Hepatitis B surface antigen, and negative HCV antibody or viral load.
- •Hepatitis B: Subjects who are positive for Hepatitis B Surface Antigen are excluded. Subjects who are Hepatitis B Surface Antigen negative but hepatitis B core antibody positive must have their hepatitis B viral load checked. These subjects will be excluded if their viral load is positive at baseline. Subjects who are core antibody positive and viral load negative at baseline will be considered eligible. These subjects must be receiving antiviral prophylaxis initiated prior to lymphodepletion.
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研究组 & 干预措施
ATLCAR.CD30 cells
Phase Ib: In adults, and separately, in children, two doses will be investigated 1x10^8 cells/m2 and 2x10^8 cells/m^2. The study team will run two independent dose-escalation sequences, one for adults and another one for children. The study team plans to use the 3+3 design and start with a low dose of 1x10^8 cells/m2. If there are no DLT in first 3 patients, the study team will go up to the dose of 2 x 10^8 cells/m2. If there is toxicity in 1/3 patients in the initial cohort, the study team would expand to enroll up to 6 patients. If there are dose limiting toxicities (DLT) at the dose of 2 x 10^8 cells/m^2, the study team will initially decrease the dose to an intermediate dose of 1.5 x 10^8 cells/m^.
Phase II: The study team planning to enroll 31 patients to contribute data. Sequential boundary will be used to monitor DLT rate.
干预措施: ATLCAR.CD30 cells (Biological)
结局指标
主要结局
Number of participants with adverse events as a measure of safety and tolerability of ATLCAR.CD30 cells to establish a safe dose after lymphodepletion with bendamustine in adult patients
时间窗: 6 weeks
Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE
Number of participants with adverse events as a measure of safety and tolerability of ATLCAR.CD30 cells to establish a safe dose after lymphodepletion after lymphodepletion with bendamustine and fludarabine in pediatric patients
时间窗: 6 weeks
Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE
2 year progression free survival (PFS) after administration of ATLCAR.CD30 in combined adult/pediatric patients with CD30+ refractory/relapsed HL and NHL.
时间窗: 2 years
PFS is defined from day of ATLCAR.CD30 infusion to relapse (in patients with a documented complete response at time of cell infusion) or progression (in patients without complete response at time of cell infusion), or death as a results of any cause per the Lugano classification.
次要结局
- 2 year overall survival (OS) after administration of ATLCAR.CD30 transduced ATl following lymphodepletion with bendamustine in adult patients with CD30+ refractory/relapsed HL and NHL(2 years)
- Objective response rate as defined by the Lugano classification for CAR.CD30 transduced ATL following lymphodepletion with bendamustine and fludarabine when administered in adult and pediatric patients with CD30+ relapsed/refractory HL and NHL.(6 weeks)
- Adverse events associated with CAR.CD30 transduced ATL when administered in adult and pediatric patients with CD30+ relapsed/refractory HL and NHL.(6 weeks)
- 2 year overall survival (OS) after administration of CAR.CD30 transduced ATL following lymphodepletion with bendamustine and fludarabine in adult and pediatric patients with CD30+ relapsed/refractory HL and NHL.(2 years)
- Objective response rate as defined by the Lugano Classification for CAR.CD30 transduced ATL following lymphodepletion with bendamustine when administered in adult patients with CD30+ relapsed/refractory HL and NHL(6 weeks)
- 2 year progression free survival after administration of ATLCAR.CD30 following lymphodepletion with bendamustine in adult patients with CD30+ in adult patients with CD30+ refractory/relapsed HL and NHL.(2 years)
- 2 year progression free survival after administration of ATLCAR.CD30 following lymphodepletion with bendamustine and fludarabine in adult and pediatric patients with CD30+ refractory/relapsed HL and NHL.(2 years)
- Duration of response after administration of CAR.CD30 transduced ATL following lymphodepletion with bendamustine in adult patients with CD30+ relapsed/refractory HL and NHL.(15 years)
- Duration of response after administration of CAR.CD30 transduced ATL following lymphodepletion with bendamustine and fludarabine in adult and pediatric patients with CD30+ relapsed/refractory HL and NHL.(15 years)
- Number of participants with adverse events as a measure of safety and tolerability of bendamustine and fludarabine as lymphodepleting agents(6 weeks)
- Survival of ATLCAR.CD30 in vivo when infused after lymphodepletion with bendamustine.(15 years)
- Measure patient reported quality of life using the PROMIS Physical Function (PROMIS Physical Function SF20a) at baseline and over time in adult patients treated with CAR.CD30 T cells.(15 years)
- Number of adverse events as a measure of safety and tolerability of bendamustine and fludarabine as lymphodepleting agents prior to infusion of CAR.CD30 transduced ATLs in pediatric patients.(6 weeks)
- Measure patient-reported symptoms using selected symptom items from the NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) at baseline and over time in adult patients treated with CAR.CD30 T cells.(15 years)
- Measure patient-reported quality of life using the PROMIS Global Health (PROMIS GHS SF v1.0-1.1) at baseline and over time in adult patients treated with CAR.CD30 T cells.(15 years)
- To measure the survival of ATLCAR.CD30 in vivo when infused after lymphodepletion with bendamustine and fludarabine.(15 years)