Clinical Trials /

Administration of Anti-CD19-chimeric-antigen-receptor-transduced T Cells From the Original Transplant Donor to Patients With Recurrent or Persistent B-cell Malignancies After Allogeneic Stem Cell Transplantation

NCT01087294

Description:

Background: - Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure that transplants bone marrow cells (stem cells) from a matching donor into a recipient in order to allow the donor stem cells to produce cells that will attack the recipient s cancer cells. AlloHSCT is performed when chemotherapy, immunotherapy, or radiation therapy do not adequately control cancer growth. However, cancers that are not controlled by alloHSCT frequently become resistant to other standard treatment options. - The outcomes of alloHSCT might be improved if certain kinds of white blood cells (T cells) could be manipulated so that they generate a more potent effect against the cancer cells. This effect can be augmented by genetically engineering donor T cells to specifically recognize cancerous cells in order to attack them. For this purpose, researchers are studying a specific kind of genetically engineered T cell known as the anti-CD19-CAR-transduced T cell. More research is needed to determine if this T cell will be an effective treatment for certain kinds of B cell cancer (such as non-Hodgkin s lymphoma and chronic lymphocytic leukemia) that has not been controlled with alloHSCT. Objectives: - To assess the safety and effectiveness of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell cancer that has not responded to alloHSCT. Eligibility: - Individuals between 18 and 75 years of age who have received allogeneic hematopoietic stem cell transplantation for a B cell cancer, but whose cancer has either not responded to or recurred after the transplant. - Recipients must have the same stem cell donor from their previous procedure. Design: - Before the start of the study, all participants will be screened with a medical history and blood tests. Recipients will have tumor imaging scans, additional blood tests, and other tests as directed by the study doctors. - Donor participants will undergo apheresis to provide white blood cells for researchers to use in the treatment. - Recipients will have dose escalation to determine the most effective yet safe dose of anti-CD19 T cells. There will be six dose levels of anti-CD19 T cells. The first patients enrolled will have the smallest dose, and the dose will be increased when a level has been determined to be safe. . - Recipients will be hospitalized for at least 9 days after receiving the cell infusion, and will need to come to clinic for follow-up visits 2, 4, 8, and 12 weeks after the infusion. - Additional scans and frequent blood tests will be required for the first 3 months after the infusion, followed by less frequent visits over time. - Recipients will be followed for a maximum of 15 years after receiving the infusion.

Related Conditions:
  • B-Cell Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Administration of Anti-CD19-chimeric-antigen-receptor-transduced T Cells From the Original Transplant Donor to Patients With Recurrent or Persistent B-cell Malignancies After Allogeneic Stem Cell Transplantation
  • Official Title: Administration of Anti-CD19-Chimeric-Antigen-Receptor-Transduced T-cells From the Original Transplant Donor to Patients With Recurrent or Persistent B-Cell Malignancies After Allogeneic Stem Cell Transplantation

Clinical Trial IDs

  • ORG STUDY ID: 100054
  • SECONDARY ID: 10-C-0054
  • NCT ID: NCT01087294

Conditions

  • Leukemia, B-cell
  • Lymphoma, Hodgkins
  • Lymphoma, Non-hodgkins
  • Lymphoma, B-Cell

Interventions

DrugSynonymsArms
Anti-CDl9-chimeric- antigen-receptor- transduced T cells1A/T cell arm (closed)

Purpose

Background: - Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure that transplants bone marrow cells (stem cells) from a matching donor into a recipient in order to allow the donor stem cells to produce cells that will attack the recipient s cancer cells. AlloHSCT is performed when chemotherapy, immunotherapy, or radiation therapy do not adequately control cancer growth. However, cancers that are not controlled by alloHSCT frequently become resistant to other standard treatment options. - The outcomes of alloHSCT might be improved if certain kinds of white blood cells (T cells) could be manipulated so that they generate a more potent effect against the cancer cells. This effect can be augmented by genetically engineering donor T cells to specifically recognize cancerous cells in order to attack them. For this purpose, researchers are studying a specific kind of genetically engineered T cell known as the anti-CD19-CAR-transduced T cell. More research is needed to determine if this T cell will be an effective treatment for certain kinds of B cell cancer (such as non-Hodgkin s lymphoma and chronic lymphocytic leukemia) that has not been controlled with alloHSCT. Objectives: - To assess the safety and effectiveness of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell cancer that has not responded to alloHSCT. Eligibility: - Individuals between 18 and 75 years of age who have received allogeneic hematopoietic stem cell transplantation for a B cell cancer, but whose cancer has either not responded to or recurred after the transplant. - Recipients must have the same stem cell donor from their previous procedure. Design: - Before the start of the study, all participants will be screened with a medical history and blood tests. Recipients will have tumor imaging scans, additional blood tests, and other tests as directed by the study doctors. - Donor participants will undergo apheresis to provide white blood cells for researchers to use in the treatment. - Recipients will have dose escalation to determine the most effective yet safe dose of anti-CD19 T cells. There will be six dose levels of anti-CD19 T cells. The first patients enrolled will have the smallest dose, and the dose will be increased when a level has been determined to be safe. . - Recipients will be hospitalized for at least 9 days after receiving the cell infusion, and will need to come to clinic for follow-up visits 2, 4, 8, and 12 weeks after the infusion. - Additional scans and frequent blood tests will be required for the first 3 months after the infusion, followed by less frequent visits over time. - Recipients will be followed for a maximum of 15 years after receiving the infusion.

Detailed Description

      BACKGROUND:

      Many patients with advanced B-cell malignancies that cannot be cured by chemotherapy and
      monoclonal antibodies have prolonged relapse-free survival after allogeneic hematopoietic
      stem cell transplantation (alloHSCT); however, a substantial fraction of patients with B-cell
      malignancies relapse following alloHSCT.

      The first therapeutic maneuver attempted when patients without graft-versus-host disease
      (GVHD) relapse after alloHSCT is usually withdraw of immunosuppressive drugs. If a remission
      does not occur after withdraw of immunosuppression, patients are often treated with donor
      lymphocyte infusions (DLI). Withdraw of immunosuppression and DLI can lead to complete
      remissions in patients with B-cell malignancies that relapse after alloHSCT. Unfortunately, a
      substantial fraction of patients do not enter a complete remission after withdraw of
      immunosuppression followed by DLI, and these therapies are often complicated by GVHD.

      The outcomes of alloHSCT might be improved if T cells could be manipulated so that they
      generate a more potent graft-versus-malignancy (GVM) effect than unmanipulated T cells.

      We hypothesize that the GVM effect against B-cell malignancies can be augmented by
      genetically engineering donor T cells to express receptors that specifically recognize
      antigens expressed by malignant B cells.

      Chimeric antigen receptors (CARs) consist of an antigen recognition moiety combined with
      T-cell signaling domains. CARs are capable of activating T cells in an antigen-specific
      manner.

      Expression of the CD19 antigen is limited to B cells and perhaps follicular dendritic cells.
      Most malignant B cells express CD19.

      We have constructed a retroviral vector encoding an anti-CD19 CAR. Large numbers of T cells
      that have been transduced with this retroviral vector can be generated in vitro for clinical
      adoptive T cell therapy. These anti-CD19-CAR-transduced T cells specifically recognize a
      variety of CD19+ target cells and kill primary chronic lymphocytic leukemia (CLL) cells in
      vitro.

      PRIMARY OBJECTIVE:

      To assess the safety of administering allogeneic anti-CD19-CAR-transduced T cells to patients
      with B-cell malignancies that are persistent or relapsed after alloHSCT. The allogeneic
      anti-CD19-CAR-transduced T cells will be derived from the original allogeneic transplant
      donor.

      ELIGIBILITY:

      Patients with any CD19-expressing malignancy that is persistent or recurrent following
      successful T-cell engraftment after HLA-identical or 9/10 matched sibling, 1-antigen
      mismatched related, or greater than or equal to 9/10-matched unrelated donor (URD) alloHSCT
      and sequential treatment with withdraw of immunosuppression and DLI. Patients with acute
      lymphoblastic leukemia (ALL). ALL -like high grade lymphomas, Burkitt lymphoma or diffuse
      large B-cell lyphoma will be eligibile after alloHSCT and withdraw of immunosuppression
      whether or not they have received a DLI.

      The same donor that provided cells for the alloHSCT must be willing and able to undergo
      leukapheresis so that cells can be obtained to prepare the anti-CD19-CAR-transduced T cells.

      The recipient must have at most grade I acute GVHD (see Appendix 1) or at most mild global
      score chronic GVHD (see Appendix 9). The recipient must not have received systemic
      immunosuppressive drugs for at least 28 days at the time of study enrollment. Patients must
      be on a dose of corticosteroids of an equivalent of 5 mg/day or less of prednisone.

      DESIGN:

        -  The alloHSCT donor will undergo leukapheresis.

        -  Patients will undergo apheresis to obtain peripheral blood mononuclear cells. These
           cells will be processed to produce anti-CD19 CAR stem memory T cells (anti-CD19 CAR
           Tscm). This process involves sorting the cells and then culturing the cells in vitro for
           9 days. During the 9-day culture period, the cells will be transduced with
           gammaretroviruses encoding the FMC63-28Z.

        -  CAR recipients will be monitored for development of acute treatment-related toxicities
           for at least 9 days after cell infusion as inpatients. Dose-limiting toxicities (DLTs)
           will include severe acute GVHD and Grade 4 toxicities not associated with GVHD.

        -  A maximum of 126 evaluable patients (donors plus recipients) will be treated.

        -  Assessment of safety is a primary objective of this clinical trial. Safety will be
           defined as a lack of severe acute post-infusional toxicities and an incidence of GVHD
           that is not higher than historical rates of GVHD occurring after standard DCI.

        -  Anti-CD19-CAR-transduced T-cell persistence in the peripheral blood will be measured at
           multiple time points from 1 week to 1 year after anti-CD19-CARtransduced T cell infusion
           by flow cytometry.

        -  To assess for an anti-malignancy effect of the infused cells, patients will be staged
           using standard staging systems.
    

Trial Arms

NameTypeDescriptionInterventions
1A/T cell arm (closed)ExperimentalDose escalation of CAR+ T cells based on the patients actual body weight
  • Anti-CDl9-chimeric- antigen-receptor- transduced T cells
1B/T memory stem celll armExperimentalDose escalation with 6 dose levels of CAR+ T memory cells based on the patients actual body weight
  • Anti-CDl9-chimeric- antigen-receptor- transduced T cells
2/Donor armOtherLeukapheresis

    Eligibility Criteria

            -  INCLUSION CRITERIA:
    
            Inclusion Criteria: Recipient
    
              1. Recipients (patients with B-cell malignancy) must have received an HLA-identical or
                 9/10 matched sibling allogeneic hematopoietic stem cell transplant, a 1-antigen
                 mismatched related transplant, or a greater than or equal to 9/10-matched unrelated
                 donor (URD) alloHSCT for any CD19+ B-cell malignancy. Patients with any CD19+ B-cell
                 malignancy that is persistent or relapsed after all of the following interventions are
                 eligible:
    
                   1. Donor T cell engraftment after alloHSCT (>50% donor chimerism of the T cell
                      compartment and a peripheral blood T cell number from the NIH, CC clinical lab of
                      at least 50 CD3+ cells/uL).
    
                   2. A trial of withdrawal of immunosuppressive therapy.
    
                   3. At least one donor cell infusion (DCI) with a minimum T cell dose of 5 times
                      10(6) CD3+ cells/kg.
    
                 Exception: Prior (DCI) DLI is not an eligibility requirement for patients with ALL,
                 Burkitt lyphoma, ALL like high-grade lymphomas, or diffuse large B-cell lymphoma.
    
                 At least 28 days weeks must have elapsed since the latest trial of withdraw of
                 immunosuppression or DLI until the patient can be deemed to have persistent disease.
    
              2. CD19 expression must be detected on the majority of the malignant cells by
                 immunohistochemistry or by flow cytometry in the Laboratory of Pathology, CCR, NCI,
                 NIH. Definition of which cells are malignant must be determined for each patient by
                 the Laboratory of Pathology using techniques to demonstrate monoclonality such as
                 kappa/lambda restriction (other techniques can be used to determine monoclonality at
                 the discretion of the Laboratory of Pathology). The choice of whether to use flow
                 cytometry or immuohistochemistry will be determined by what is the most easily
                 available tissue sample in each patient. Immunohistochemistry will be used for lymph
                 node biopsies and bone marrow biopsies. Flow cytometry will be used for peripheral
                 blood, fine needle aspirate, and bone marrow aspirate samples.
    
              3. Patients must be 18-75 years of age.
    
              4. Performance status: ECOG less than or equal to 2
    
              5. Either no evidence of GVHD or minimal clinical evidence of acute GVHD and chronic GVHD
                 while off of systemic immunosuppressive therapy for at least 28 days. Minimal clinical
                 evidence of acute GVHD is defined as grade 0 to I acute GVHD. Minimal evidence of
                 chronic GVHD is defined as mild global score chronic GVHD (as defined by the 2005 NIH
                 consensus project) or no chronic GVHD. Subjects with disease that is controlled to
                 stage I acute GVHD or to mild global score chronic GVHD with local therapy only, e.g.,
                 topical cutaneous steroids or oral budesonide, will be eligible for enrollment.
    
              6. Ability to give informed consent.
    
              7. Prior Therapy: Therapy with monoclonal antibodies and/or chemotherapy must be stopped
                 at least 7 days prior to anti-CD19 CAR-transduced T cell infusion, and recovery of
                 treatment-associated toxicity to less than or equal to grade 2 is required prior to
                 infusion of cells. For patients that have received prior DLI, the last dose must be at
                 least 28 days prior to anti-CD19 CAR-transduced T cell administration. Note that
                 patients can be enrolled on this study at any time after or during therapy, but at
                 least 14 days must elapse from the time of prior monoclonal antibody administration or
                 chemotherapy until anti-CD19 CAR-transduced T cells are infused, and at least 28 days
                 must elapse from the time of withdraw of immunosuppression, or DLI, or other
                 immunomodulatory therapies such as lenalidomide until anti-CD19 CAR-transduced T cells
                 are infused. Systemic immunosuppression must be stopped at least 28 days prior to
                 protocol entry. There is no time restriction in regard to prior intrathecal
                 chemotherapy provided there is complete recovery from any acute toxic effects of such.
    
              8. Recipients of unrelated donor transplants from a National Marrow Donor Program (NMDP)
                 Center must sign a release of information form to authorize NMDP transfer of
                 information to the NIH.
    
              9. Previous allogeneic donor must be willing and available to donate again.
    
             10. Patients of childbearing or child-fathering potential must be willing use an effective
                 method of contraception while being treated on this study and for 4 months after the
                 last cell infusion.
    
             11. Normal left ventricular function as evaluated by echocardiograph within 4 weeks of
                 anti- CD19-CAR-transduced T cell infusion
    
            Inclusion Criteria: Donor
    
              1. Donors greater than or equal to 18 years of age must be the same individual whose
                 cells were used as the source for the patient s original stem cell transplant.
    
              2. Adequate venous access for peripheral leukapheresis, or consent to use a temporary
                 central venous catheter for leukapheresis.
    
              3. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C
                 antibody negative.
    
              4. Ability to give informed consent.
    
              5. Donor selection will be in accordance with NIH/CC Department of Transfusion Medicine
                 (DTM) criteria and, in the case of an unrelated donor from a Transplant Center, the
                 National Marrow Donor Program (NMDP) standards. When a potentially eligible recipient
                 of an unrelated donor product from an NMDP Center is identified, the recipient will
                 complete an NMDP search transfer request to allow NIH NMDP staff to contact the NMDP
                 Coordinating Center, who will, in turn, contact the donor s prior Donor Center. The
                 NMDP Policy for Subsequent Donation Requests will be followed and the appropriate
                 forms (Subsequent Donation Request form) and Therapeutic T Cell Collection
                 Prescription will be submitted as required.
    
            EXCLUSION CRITERIA:
    
            Exclusion Criteria: Recipients
    
              1. Active infection that is not responding to antimicrobial therapy.
    
              2. Evidence of infection with HIV, Hepatitis B or Hepatitis C. Patients must be HIV
                 negative, Hepatitis B surface antigen, and Hepatitis C antibody negative. The high
                 degree of immune suppression that may be used in this study may lead to the activation
                 or progression of these viral illnesses.
    
              3. Active psychiatric disorder which may compromise compliance with the treatment
                 protocol, or which does not allow for appropriate informed consent (as determined by
                 Principal Investigator and/or his designee).
    
              4. Pregnant or lactating. The effects of the immunosuppressive medications that could be
                 required to treat GHVD are likely to be harmful to a fetus. The effects upon breast
                 milk are also unknown and may be harmful to an infant.
    
              5. Serum total bilirubin > 2.5 mg/dl, serum ALT and AST values greater than or equal to
                 2.5 times the upper limit of normal based on age-specific normal values. If the
                 abnormal liver function is attributable to liver involvement by malignancy, patients
                 may be eligible with serum total bilirubin up to 5.0 mg/dl, and serum ALT and AST
                 values up to 5.0 times the upper limit of normal, provided the patient has no evidence
                 of impending hepatic failure (encephalopathy or prothrombin time >2 times the upper
                 limit of normal).
    
              6. Serum creatinine greater than 1.6 mg/dL
    
              7. Absolute neutrophil count of less than 1000 cells/microL unless low neutrophil count
                 is thought to be due to malignancy in the bone marrow and malignancy is documented in
                 the bone marrow.
    
              8. Active cerebrospinal fluid involvement with malignancy or brain metastasis.
    
              9. Platelet count less than 30,000/microL unless low platelet count is thought to be due
                 to malignancy in the bone marrow and malignancy is documented in the bone marrow.
    
             10. Hemoglobin less than 8.0 g/dL.
    
             11. Receiving corticosteroids above physiological dosing (greater than 5mg per day of
                 prednisone) within 28 days prior to anti-CD19-CAR-transduced T cell administration.
    
            Exclusion Criteria: Donors
    
              1. History of psychiatric disorder which may compromise compliance with this protocol or
                 which does not allow for appropriate informed consent.
    
              2. History of hypertension that is not controlled by medication, stroke, or severe heart
                 disease (donors with symptomatic angina will be excluded). Donors with a history of
                 coronary artery bypass grafting or angioplasty who are symptom free will receive a
                 cardiology evaluation and be considered on a case-by-case basis.
    
              3. Donors must not be pregnant.
    
              4. Anemia (Hb < 11 gm/dl) or thrombocytopenia (platelets < 100,000 per microL). However,
                 potential donors with Hb levels < 11 gm/dl that is due to iron deficiency will be
                 eligible as long as the donor is initiated on iron replacement therapy. The NIH
                 Clinical Center, Department of Transfusion Medicine/NMDP physicians will determine the
                 appropriateness of individuals as donors.
          
    Maximum Eligible Age:75 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:Accepts Healthy Volunteers

    Primary Outcome Measures

    Measure:To assess the safety of allogeneic anti-CD19-CAR
    Time Frame:4-5 weeks after the first dose
    Safety Issue:
    Description:List of adverse event frequency

    Secondary Outcome Measures

    Measure:To determine if administering anti-CD19-CAR-transduced T cells from the original transplant donor can cause regression of B-cell malignancies that are relapsed or persistent after alloHSCT
    Time Frame:At progression
    Safety Issue:
    Description:Median amount of time subject survives without disease progression after treatment
    Measure:To measure the persistence of anti-CD 19-CAR-transduced T cells in the blood of patients after infusion
    Time Frame:Until the patient goes off-study for malignancy response assessment
    Safety Issue:
    Description:Amount of anti-CD19-CAR-transduced T cells in the blood of patients after infusion.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Trial Keywords

    • CD19
    • Chimeric-Antigen-Receptor
    • Gene Therapy
    • Adoptive T Cell Therapy
    • Allogeneic Stem Cell Transplantation

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