A Phase 1/2 Trial Evaluating Treatment of Emergent Graft Versus Host Disease (GvHD) With AP1903 After Planned Donor Infusions (DLIs) of T-cells Genetically Modified With the iCasp9 Suicide Gene in Patients With Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- To Evaluate the Safety of Donor Lymphocyte Infusion Followed by Dimerizer Drug, AP1903 by Number of Participants With Adverse Events.
研究概览
简要总结
The goal of this clinical research study is to learn if giving genetically changed immune cells, called T-cells, after chemotherapy will improve the response to a stem cell transplant. The safety of this treatment will also be studied.
The process of changing the DNA (the genetic material in cells) of these T-cells is called "gene transfer." Researchers want to learn if these genetically-changed T-cells are effective in attacking cancer cells in patients with leukemia, MDS, lymphoma, Hodgkin disease, or MM, after they have received an allogeneic stem cell transplant.
The chemotherapy you will be given on study is fludarabine, melphalan, and alemtuzumab. These drugs are designed to stop the growth of cancer cells, which may cause the cancer cells to die. This chemotherapy is also designed to block your body's ability to reject the donor's stem cells.
Researchers also want to learn if giving AP1903 will help the symptoms of graft-versus-host disease (GvHD) that may occur after the T-cell infusion. GvHD occurs when donor cells attack the cells of the person receiving the stem cell transplant.
详细描述
Gene Transfer:
Gene transfer involves drawing blood from a transplant donor, and then separating out the T-cells using a machine. Researchers then perform a gene transfer to change the T-cells' DNA, and then inject the changed T-cells into the body of the patient receiving the transplant.
Study Drug Administration:
You will receive fludarabine, melphalan, and alemtuzumab to kill cancer cells and help prevent your body from rejecting the stem cells. The day you receive the stem cells is called Day 0. The days before you receive your stem cells are called minus days. The days after you receive the stem cells are called plus days.
On Day -7, you will be admitted to the hospital and given fluids by vein to hydrate you.
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >/= 18 years and </= 65 years.
- •One of the following: a. Acute leukemia past first remission, in first or subsequent relapse, in second or greater remission. Patients in first remission should have with intermediate or high cytogenetic risk factors or flt3 mutation. Patients with relapsed disease. Patients with primary induction failure or relapse are eligible if they have < 10% bone marrow blasts, and no circulating blasts. b. Myelodysplastic syndrome with intermediate or high risk IPSS score, or treatment related MDS. c. CML resistant to tyrosine kinase treatment in a first or subsequent chronic phase or after transformation to accelerated phase or blast crisis.
- •2 (continued): d. CLL, Lymphoma or Hodgkin's disease which has failed to achieve remission or recurred following initial chemotherapy. Patients must have at least a PR to salvage therapy, or low bulk untreated relapse (< 2 cm largest mass). e. Multiple myeloma which has relapsed or progressed and has achieved a partial response to salvage chemotherapy.
- •Patients must have one of the following donor types identified who are willing to donate peripheral blood: a. Related donor, 8/8 HLA-matched for HLA-A, -B, C and DR matched or, b. Matched Unrelated Donor (MUD), 8/8 HLA-matched for HLA A, B, C and DRB1 using allele level typing.
- •Performance score of at least 80% by Karnofsky.
- •Adequate major organ system function as demonstrated by: a. Creatinine < 1.8 mg/dl (or creatinine clearance > 40 ml/min) b. Bilirubin < 1.5 mg/dl except for Gilbert's disease c. ALT < 300 IU/ml d. Left ventricular ejection fraction equal or greater than 40%. e. Pulmonary function test (PFT) demonstrating a diffusion capacity of least 50% predicted, corrected for hemoglobin.
- •Patient or patient's legal representative, able to sign informed consent.
- •Patient or patient's legal representative, parent(s) or guardian able to provide written informed consent for the long-term follow-up gene therapy study 2006-
- •The patient will need to be available for evaluation within 72 hours of symptoms of GVHD, occurring within 60 days of the planned donor lymphocyte infusion.
排除标准
- •Uncontrolled active infection.
- •Positive Beta HCG test in a woman with child bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization.
- •Women of child bearing potential not willing to use an effective contraceptive measure while on study.
- •Men not willing to use an effective contraception method while on study.
- •Known sensitivity to any of the products that will be administered during the study.
- •HIV seropositive.
- •Prior allogeneic transplant.
研究组 & 干预措施
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: Fludarabine (Drug)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: Melphalan (Drug)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: Alemtuzumab (Drug)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: Stem Cell infusion (Procedure)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: Tacrolimus (Drug)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: Mini Methotrexate (Drug)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: G-CSF (Drug)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: Donor Lymphocyte Infusion (DLI) (Procedure)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: AP1903 (Drug)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: Methylprednisolone (Drug)
Stem Cell Transplant + Modified T-Cells + Chemotherapy
The first component is stem cell transplant. Goal is to administer more than 3 x 106 CD34+ cells/kg of peripheral blood progenitor cells (PBPC). The second component is the planned DLI infusion. iCasp9 (BPZ-1001)-Modified T-cells) of 3 X 10^6/kg in 100 ml infused over approximately a one hour period between Day + 56 to Day +64. The transplant day is referred to as day zero (D0), treatment plan activities prior or after D0 are denoted as day minus (D-) or day plus (D+). Patients receive standard reduced intensity regimen using fludarabine, melphalan, and alemtuzumab to achieve engraftment with a low risk of GVHD. At approximately 60 days post transplant patients who are alive and without GVHD, receive DLI to enhance graft-vs.-malignancy and immune reconstitution.
干预措施: Questionnaire (Behavioral)
结局指标
主要结局
To Evaluate the Safety of Donor Lymphocyte Infusion Followed by Dimerizer Drug, AP1903 by Number of Participants With Adverse Events.
时间窗: up to 3.5 years
To evaluate the safety of the infusion of inducible caspase 9 (BPZ-1001) modified T-cells followed by dimerizer drug, AP1903. Safety evaluated by number of participants with Adverse events.
次要结局
- Number of Participants Assessed Post Donor Lymphocyte Infusion (DLI): Disease-free Survival & Non-relapse Mortality, Chimerism and GVHD.(6 months)
- To Assess the Incidence of Epstein-Barr Virus -PTLD or EBV Reactivation Requiring Therapy Post DLI.(1 year)
- To Assess the Proportion of Patients Developing Grade I-IV Acute GvHD(Day 28, 56, and 180 post DLI.)
- To Assess the Proportions of GvHD Response Post-administration of AP1903.(Day 3, 7, 14, 28, and 56 post-administration of AP1903)
- To Assess the Incidence of GvHD Treatment Failure Post-administration of AP1903.(Day 3, 7, 14, 28, and 56 post-administration of AP1903.)
- To Assess the Incidence of Acute GvHD Flare After CR/PR Requiring Additional Agent for Systemic Therapy Before Day 56 Post-administration of AP1903.(before Day 56 post AP1903)
- To Assess Post Donor Lymphocyte Infusion (DLI) Chimerism(6 months)