Clinical Trials /

Donor Lymphocyte Infusion (DLI) of T-cells Genetically Modified With iCasp9 Suicide Gene

NCT01875237

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Donor Lymphocyte Infusion (DLI) of T-cells Genetically Modified With iCasp9 Suicide Gene
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 2012-0501
  • SECONDARY ID: NCI-2013-01666
  • NCT ID: NCT01875237

Conditions

  • Leukemia
  • Myeloma
  • Myeloproliferative Diseases

Interventions

DrugSynonymsArms
FludarabineFludarabine phosphate, FludaraStem Cell Transplant + Modified T-Cells + Chemotherapy
MelphalanAlkeranStem Cell Transplant + Modified T-Cells + Chemotherapy
AlemtuzumabCAMPATH-1H, CampathStem Cell Transplant + Modified T-Cells + Chemotherapy
TacrolimusPrografStem Cell Transplant + Modified T-Cells + Chemotherapy
Mini MethotrexateStem Cell Transplant + Modified T-Cells + Chemotherapy
G-CSFFilgrastim, NeupogenStem Cell Transplant + Modified T-Cells + Chemotherapy
AP1903Stem Cell Transplant + Modified T-Cells + Chemotherapy
MethylprednisoloneDepo-Medrol, Medrol, Solu-MedrolStem Cell Transplant + Modified T-Cells + Chemotherapy

Purpose

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.

Detailed Description

      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.

      On Days -6 through -3, you will receive fludarabine by vein over 1 hour each day.

      On Day -2, you will receive melphalan by vein over 30 minutes.

      On Day -1, you will receive alemtuzumab by vein over 2 hours.

      On Day 0, you will receive the stem cell transplant as a cell infusion by vein.

      After the transplant, you will receive tacrolimus and methotrexate. At first, you will
      receive tacrolimus as a continuous (nonstop) infusion until you are able to take it by mouth.
      You will then take tacrolimus by mouth 2 times a day for about 3 weeks and then your doctor
      will tell you how to taper it off (gradually stop taking it). On Days +1, +3, +6, and +11,
      you will receive methotrexate by vein over 30 minutes.

      You will receive filgrastim as an injection under the skin 1 time a day, starting 1 week
      after the transplant, until your blood cell levels return to normal. Filgrastim is designed
      to help with the growth of white blood cells.

      Between Day +56 and +64, if you are in stable medical condition and have not developed GvHD,
      you will receive a donor lymphocyte infusion containing genetically modified T-cells by vein
      over 10-30 minutes. You will receive Benadryl (diphenhydramine) by vein over 15 minutes and
      Tylenol by mouth before the infusion to lower the risk of an allergic reaction.

      If your doctor thinks it is needed due to medical problems, the T-cell infusion may be
      postponed for up to 6 months after the transplant.

      If you develop symptoms of GvHD after the T-cell infusion, you must return to the clinic
      within 72 hours. Most cases of GVHD occur within 60 days of the T-cell infusion. If you have
      GvHD, you will receive AP1903 by vein and possibly steroids by mouth or by vein. If your
      doctor thinks it is needed, you may receive one more dose of AP1903 by vein 24-72 hours after
      the first dose.

      If GvHD returns after the first treatment and your doctor thinks it is needed, you may
      receive AP1903 by vein and steroids by mouth or by vein.

      Blood (about 2 tablespoons each time) will be drawn about 3 hours before you receive AP1903,
      about 2 hours after the AP1903 infusion, and then about 24 hours after the AP1903 infusion to
      check the level of genetically modified T-cells.

      You will then come to the clinic every day for the next 3 days and for an additional 3 days
      after a second dose of AP1903, if given. In addition, you will come to the clinic on about
      Days +7, +14, +28, +42 and +56 after receiving AP1903. If your symptoms do not improve after
      receiving AP1903, you will be given standard drugs for GvHD.

      Study Tests:

      After the stem cell transplant but before the T-cell infusion, you will have the following
      tests and procedures to find out if you will be eligible for the T-cell infusion:

        -  You will have a physical exam.

        -  You will be checked for possible reactions to treatment, including GvHD.

        -  Blood (about 4 tablespoons) will be drawn for routine tests, to check your liver and
           kidney function, for chimerism studies (determination of donor or recipient cells), and
           to check for cytomegalovirus (CMV).

        -  If your doctor thinks it is needed, you will have a bone marrow aspiration and biopsy
           performed to check the status of the disease. To collect a bone marrow
           aspiration/biopsy, an area of the hip is numbed with anesthetic, and a small amount of
           bone marrow and bone is withdrawn through a large needle.

      About twice a week until about 2 months after the T-cell infusion, and then 6 and 12 months
      after the stem cell transplant:

        -  You will have a physical exam, including measurement of your height, weight and vital
           signs.

        -  Your medical history will be recorded.

        -  You will have be checked for possible reactions to your treatment, including GvHD.

        -  Blood (about 4 tablespoons) will be drawn for routine tests, to check your liver and
           kidney function, and to check for CMV and other infections. Part of the blood may be
           used for chimerism studies, if your doctor thinks it is needed.

        -  If your doctor thinks it is needed, you may have a bone marrow aspiration and biopsy
           performed to check the status of the disease and for chimerism studies.

      If your doctor thinks it is needed, some tests and procedures may be repeated more frequently
      or at different time points during the study.

      Immune System and T-cell Level Tests:

      If possible, blood (about 3 tablespoons) will be drawn to check the status of the disease and
      your immune system function:

        -  4 hours after the T-cell infusion,

        -  once a week for 1 month after the T-cell infusion,

        -  and then at 6 weeks and then about 2, 3, 6, 9, and 12 months after the T-cell infusion.
           °Part of the blood sample will be used to check for HAMA at 3 months after the T-cell
           infusion.

      Part of the blood drawn will be tested to check the level and function of the infused
      T-cells. At 3 months after the T-cell infusion, blood (about 1 teaspoon) will be drawn to
      check for HAMA.

      Questionnaires:

      You will complete a quality of life questionnaire that will take about 5-10 minutes each
      time:

        -  When you enroll on this study

        -  At the time of the T-cell infusion

        -  If you develop symptoms of GvHD after the T-cell infusion and receive AP1903, you will
           complete the questionnaire before you receive AP1903, and then about 7 and 14 days after
           you receive AP1903.

        -  If you do not develop symptoms of GvHD, you will complete a questionnaire about 1 month
           after the T-cell infusion.

      Length of Treatment:

      You will be off study after your 1-year follow-up visit. You will be taken off study early
      if:

        -  not enough donor cells could be collected

        -  you were not eligible to receive the T-cell infusion

        -  you have graft failure (the donor cells did not "take")

        -  the disease comes back and needs another treatment

        -  you are unable to keep appointments

        -  you did not return to the clinic within 72 hours of having symptoms of GvHD

        -  your study doctor thinks it is in your best interest

      If you are taken off study, you will receive standard of care treatment.

      Long-Term Follow-Up:

      For safety reasons, the U.S. Food and Drug Administration (FDA) requires that patients who
      receive infusions of stem cells treated with a gene transfer procedure must have long-term
      follow-up yearly for at least 15 years after receiving the gene transfer.

      You will have blood tests performed to check to make sure you do not have a type of infection
      called the replication-competent retrovirus (RCR). For this test, blood (up to 4 teaspoons
      each time) will drawn about 1, 3, and 6 months after the T-cell infusion, then once every 6
      months for 5 years, and then once a year after that for 10 years.

      If the RCR test results during the first year after the T-cell infusion show that you do not
      have the RCR infection, the rest of your leftover blood samples (left over from RCR testing
      in Years 2-15) will be stored at Bellicum for safety reasons. This is so researchers can
      study any changes in your blood (related to RCR) that may arise in Years 2-15.

      You will be asked to sign a separate consent form for a long-term follow-up study, Protocol
      2006-0676. If for any reason you are unable to receive the genetically modified cells, you
      will not be enrolled on the long-term follow-up study.

      This is an investigational study. The gene transfer or infusion with genetically-changed
      T-cells and the drug, AP1903, are not FDA approved or commercially available for use in this
      type of disease. They are currently being used for research purposes only. Fludarabine,
      melphalan, and alemtuzumab are commercially available and FDA approved.

      Up to 35 patients will take part in this study. All will be enrolled at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
Stem Cell Transplant + Modified T-Cells + ChemotherapyExperimentalThe 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.
  • Fludarabine
  • Melphalan
  • Alemtuzumab
  • Tacrolimus
  • Mini Methotrexate
  • G-CSF
  • AP1903
  • Methylprednisolone

Eligibility Criteria

        Inclusion Criteria:

          1. Age >/= 18 years and </= 65 years.

          2. 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.

          3. 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.

          4. 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.

          5. Performance score of at least 80% by Karnofsky.

          6. 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.

          7. Patient or patient's legal representative, able to sign informed consent.

          8. 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 2006-0676.

          9. 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.

        Exclusion Criteria:

          1. Uncontrolled active infection.

          2. Positive Beta HCG test in a woman with child bearing potential, defined as not
             post-menopausal for 12 months or no previous surgical sterilization.

          3. Women of child bearing potential not willing to use an effective contraceptive measure
             while on study.

          4. Men not willing to use an effective contraception method while on study.

          5. Known sensitivity to any of the products that will be administered during the study.

          6. HIV seropositive.

          7. Prior allogeneic transplant.
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Graft Versus Host Disease (GVHD) Free Survival
Time Frame:180 days
Safety Issue:
Description:Probabilities of persistent GVHD free survival estimated using Kaplan-Meier estimators, with the primary analysis population defined as those patients who receive DLI, and an event defined as either death or development of acute GVHD which persists for at least 14 days or which requires steroid therapy for more than 14 days. The mean restricted time alive without persistent acute GVHD will be calculated up to day 180 for each group, and the groups will be compared using a two-sample Z statistic based on the difference in restricted means.

Secondary Outcome Measures

Measure:Disease-Free Survival (DFS)
Time Frame:6 months
Safety Issue:
Description:Disease-free survival estimated using the Kaplan-Meier estimate at 6 months post enrollment and at 6 months post DLI. The median DFS and its 95% confidence interval will also be described if reached. The disease free survival curves will be compared between the two treatment groups using the log-rank test.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Leukemia
  • Myeloma
  • Myeloproliferative Diseases
  • Myelodysplastic syndrome
  • MDS
  • Lymphoma
  • Hodgkin disease
  • Multiple myeloma
  • MM
  • Transplant donor
  • T-cells
  • G-versus-host disease
  • GvHD
  • G-CSF
  • Filgrastim
  • Neupogen
  • Fludarabine
  • Fludarabine phosphate
  • Fludara
  • Melphalan
  • Alkeran
  • Alemtuzumab
  • CAMPATH-1H
  • Campath
  • Tacrolimus
  • Prograf
  • Mini-methotrexate
  • AP 1903
  • Methylprednisolone
  • Depo-Medrol
  • Medrol
  • Solu-Medrol
  • Stem cell infusion
  • Donor lymphocyte infusion
  • DLI
  • Questionnaire
  • Survey

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